Metachromatic leukodystrophy (MIM# 250100) is a lysosomal disorder with autosomal recessive inheritance due to biallelic pathogenic variants in the ARSA gene (16). Rarely, deficiency of a sphingolipid activator protein (PSAP, MIM# 249900) that is required for the formation of the substrate–enzyme complex can result in similar clinical and radiological manifestations (16). The deficiency of the enzyme or the activator protein leads to the accumulation of sulfated glycosphingolipids in the cerebral white matter and peripheral nerves, resulting in demyelination and a progressive neurodegenerative course. Based on age at symptom onset, MLD has been classified as infantile, juvenile, and adult-onset forms. Juvenile MLD is characterized by the onset of symptoms from 3 to 16 years of age, and the occurrence of initial symptoms beyond age 16 is classified as adult MLD (16). The onset of symptoms as late as fourth or fifth decade is known. Adult-onset presentation is rare, and accounts for approximately 20% of all cases (16). Initial manifestations typically include intellectual and behavioral concerns such as personality changes, emotional lability, psychosis, and cognitive decline, followed by motor symptoms such as progressive incoordination, spasticity, seizures, and peripheral neuropathy. Misdiagnosis with schizophrenia, depression and psychosis are common in earlier stages of the disease (17). Rare presentation with isolated neuropathy is known (18). Since the sulfatides accumulate in the gallbladder, cholecystitis, gall balder polyps, and carcinoma are recognized complications (16).

MRI of the brain demonstrates symmetric confluent periventricular and deep white matter changes with a tigroid pattern that represents sparing of white matter in the perivenular regions. Corpus callosum is usually involved. White matter changes in adult onset are usually frontal predominant, and progresses later to involve parieto-occipital regions (19). Subcortical U fibers are spared in the initial stages. Variable hyperintensity is noted in DWI images. Progressive brain atrophy ensues in later stages (19). MRI scoring method has been established that helps in defining the natural history and monitoring disease response in treatment trials (20).

Low Aryl sulfatase enzyme levels can be seen with pseudodeficiencies, hence molecular confirmation is essential. Also, normal levels of the enzyme do not rule out MLD, as that could happen with activator protein deficiency. Urine sulfatides is a helpful screening test as it would be elevated in all cases of MLD regardless of the enzyme or activator protein deficiency, whereas it would be normal in pseudodeficiencies (16). Hematopoietic stem cell transplantation (HSCT) in earlier stages of adult MLD has been shown to be beneficial in arresting clinical progression (21). Gene therapy has been established for childhood-onset MLD.

Globoid cell leukodystrophy or Krabbe disease is an autosomal recessive disorder caused by biallelic pathogenic variants in GALC (MIM# 245200) or PSAP (MIM# 611722) that leads to the deficiency of the enzyme galactocerebrosidase, or its activator protein saposin (22). This deficiency results in the accumulation of galactocerebroside and psychosine that eventually leads to oligodendrocyte apoptosis and gliosis, and results in clinical symptoms. Krabbe disease is categorized as early infantile, late infantile, juvenile, and adult-onset subtypes based on the age at the onset of symptoms. Clinical and radiological presentations are quite different for each subtype (22). While early onset variant have a relentlessly progressive course with loss of acquired developmental milestones along with spasticity, seizures, visual and mental deterioration, followed by decerebrate posturing and death, juvenile and adult-onset types manifest gradually progressive spastic hemiparesis or quadriparesis, along with varying combinations of visual impairment, ataxia, and neuropathy (23).

MRI brain in juvenile and adult-onset Krabbe disease show signal changes along the corticospinal tract from the motor cortex through its path in the corpus callosum, posterior limb of the internal capsule, cerebral peduncles, and brain stem. Signal changes can be asymmetric with unilateral corticospinal tract involvement in the earlier stages corresponding to the clinical deficit, and is usually followed much later by the involvement of the contralateral side and eventual quadriparesis (23). In juvenile onset and a proportion of adult-onset types, signal changes involving the posterior periventricular and deep white matter are also characteristically seen, and can mimic adrenoleukodystrophy (Figure 2). In adult-onset Krabbe disease, the corticospinal tract involvement can be seen isolated, or in combination with the posterior periventricular white matter involvement (22, 23). Periventricular and frontal white matter involvement can be seen in later stages of the disease. An imaging scoring system is available for the objective measurement of disease extent and severity that guides in tracking the radiological progression to assess the natural history and monitor therapy (24). Rare instances of normal MRI in the symptomatic phase are known (25).

Clinical course in juvenile and adult-onset Krabbe disease is highly variable with varying periods of clinical and imaging stability (23). Measurement of blood and CSF psychosine levels can aid in assessing the disease progression (26). Hematopoietic stem cell transplantation (HSCT) is considered for mildly symptomatic individuals with later onset disease with evidence of clinical progression (27). Given the heterogeneity in the clinical presentations and the disease course, candidates for HSCT need to be considered on a case-to-case basis (27).

Alexander disease (MIM# 203450) is an autosomal-dominant leukodystrophy due to heterozygous pathogenic variants in GFAP (28, 29). The disease mechanism is considered to be a gain of function mutation that disrupts the dimerization of intermediate filaments and leads to abnormal protein accumulation and collapse of the cytoskeleton (29). Clinical presentations are known to occur across all ages, and are categorized as neonatal, infantile, juvenile, and adult forms (30). While macrocephaly and regression of attained developmental milestones with rapid neurologic deterioration to death are the characteristic clinical course with neonatal and infantile-onset forms, late-onset forms have milder clinical severity and a slower neurologic decline (30). Juvenile forms have some clinical and imaging overlap with the adult form, and this spectrum probably represents a continuum (30).

The onset of symptoms can be as late as the sixth or seventh decade of life. Clinical manifestations are predominantly localized to the brain stem with bulbar, and pseudobulbar signs with symptoms such as dysphagia, vocal cord paralysis, dysphonia, dysarthria, and palatal myoclonus, followed by pyramidal and cerebellar signs (31). Sleep disturbances, extraocular movement abnormalities, and autonomic dysfunction are common. Presentations with hemiparesis, extrapyramidal symptoms, and relapsing-remitting clinical course have been described rarely (32). Cognitive deficits and epilepsy are uncommon. Refractile vomiting and failure to thrive are seen in individuals along the juvenile onset spectrum (30). MRI brain (Figure 3) classically demonstrate T2W signal changes in the anterior portion of the medulla and dentate hilum, along with the prominent atrophy of the medulla and upper cervical cord leading to “tad pole” appearance (33). Supratentorial white matter changes are rare and includes signal changes in the frontal horn of the lateral ventricles, cysts along the ventricular wall described as “garland appearance,” and mild to moderate signal changes in cerebral white matter (34). Transient swelling of the medulla before the eventual atrophy, and tumor-like presentations have been described in the literature (35, 36). Pathologic hallmark is the finding of rosenthal fibers in astrocytes on brain biopsy or autopsy (37). Non-specific clinical presentation in adult-onset cases, as well as the brain stem changes in imaging can cause diagnostic dilemma, and hence misdiagnosis with other neurodegenerative disorders, immune/inflammatory disorders, and rarely tumors are common (37).

While penetrance appears to be complete in early-onset forms, incomplete penetrance with several asymptomatic family members and variable expressivity are known with adult-onset forms (30). Though genotype–phenotype correlations are not always possible, recurrent pathogenic variants in GFAP are known to be associated with specific age at onset phenotypes (18, 30). Treatment is essentially supportive.

LMNB1-related autosomal-dominant leukodystrophy (MIM# 169500) is a rare exclusive adult-onset progressive leukodystrophy caused by mono-allelic pathogenic variants in LMNB1 (57). Symptoms usually start from the fourth or fifth decade with autonomic symptoms including bladder and bowel dysfunction, orthostatic hypotension, temperature dysregulation, and sweating abnormalities along with tremors, cerebellar ataxia, and spasticity with gait dysfunction predominantly involving lower limbs (57). Cognitive decline and pseudobulbar symptoms typically manifest late in the disease course. Sensorineural hearing loss and worsening of gait with intercurrent illnesses have been described rarely (57).

Classic MRI brain findings include signal changes along the corticospinal tract and deep white matter changes involving frontal, parietal, and occipital lobes (57). Subcortical U fibers and periventricular rim of white matter are usually spared. The temporal lobe is usually involved later in the disease course. Symmetric T2W signal changes involving the brain stem with medial lemniscus, decussation of superior cerebellar peduncles, and middle cerebellar peduncle are typical findings (58). A trophy and signal changes of the spinal cord are also a common and early finding (59) (Figure 5).

Molecular confirmation is by the detection of heterozygous LMNB1 gene duplication or rarely deletion upstream of the LMNB1 promoter that results in the overexpression of LMNB1 protein and an abnormal nuclear envelope (60, 61). Next-generation sequencing does not reliably identify this specific molecular finding, and hence targeted analysis for duplications and deletion upstream of the LMNB1 gene is indicated in the appropriate clinical and radiological setting. Genotype-phenotype correlation have been described in a small cohort with earlier age at onset, more prominent cognitive impairment, and lack of dysautonomia in individuals with upstream deletion when compared with those with duplication (60). No curative treatment is available currently.

Gordon Holmes syndrome (MIM# 212840) is a rare, distinct autosomal recessive leukodystrophy due to biallelic pathogenic variants in RNF216 which code for E3 ubiquitin ligase (62). This was initially described as a syndromic association of cerebellar ataxia with hypogonadotropic hypogonadism (63). Endocrine manifestations usually occur in adolescence or early adulthood. Neurological manifestations are characterized by early adulthood onset progressive cerebellar ataxia with cognitive decline, chorea, behavioral issues, and spasticity (64). Brain MRI demonstrates progressive cerebellar and cerebral atrophy, with T2W hyperintense signal changes involving periventricular and subcortical white matter, globus pallidus, thalamus, and pons (Figure 6). Treatment is supportive and involves hormonal replacement (65, 66).

CSF1R-related leukoencephalopathy (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, MIM # 221820) is a primary microgliopathy with autosomal-dominant inheritance, caused by a heterozygous pathogenic variant in CSF1R (67). The age at onset of symptoms is usually in the early 40s, and the clinical course is rapid once the symptoms appear, with a reported mean disease duration of 6.8 years (68). The most common early symptoms are neuropsychiatric manifestations resembling behavioral variant fronto-temporal dementia, such as depression, anxiety, apathy, irritability, personality changes, and cognitive decline (67). This is followed by motor symptoms including progressive rigidity, bradykinesia, tremors, spasticity, ataxia, and seizures. Clinical features can rarely be predominated by motor symptoms without much behavioral or personality changes (67). Women tend to have an earlier age at the onset of clinical symptoms; however, there is no difference in the disease duration between women and men. Women with the earlier onset of symptoms usually have motor predominant clinical manifestations which are often misdiagnosed as multiple sclerosis in view of the overlap in clinical and imaging features (68). Clinical diagnostic criteria for early diagnosis and targeted genetic testing have been proposed (69).

MRI brain reveals white matter changes in subcortical, deep, and periventricular regions in an asymmetric distribution, in addition to signal changes and thinning of the corpus callosum, and cerebral atrophy with the prominence of lateral ventricles and convexity subarachnoid spaces that is more prominent over frontal and parietal regions (Figure 7). Signal changes along the corticospinal tract in the posterior limb of the internal capsule and brain stem are commonly observed. The involved white matter shows a high signal in DWI sequences that probably indicates intramyelinic edema (70). Contrast enhancement is not observed, and the posterior fossa is usually spared. MRI scoring system has been established to assess the severity and longitudinal followup (71). CT brain and high-resolution gradient echo sequences demonstrate scattered punctate calcifications of the involved white matter adjacent to the frontal horn of lateral ventricles and in the parietal subcortical regions. A characteristic finding in the sagittal view is the pattern of calcification in the pericallosal white matter that has been described as a steppingstone appearance (70).

Phenotype–genotype correlation has not been established; however, seizures were noted more commonly in individuals with pathogenic variants in the proximal kinase domain of CSF1R (67). Hematopoietic stem cell transplantation has been attempted with the stabilization of motor, cognitive, and imaging scores (72).

Neuronal intranuclear inclusion disease (MIM # 603472) is an autosomal-dominant non-vascular leukoencephalopathy manifesting in adulthood, and occurs due to heterozygous pathogenic trinucleotide GGC repeat expansions in the 5′ untranslated region of NOTCH2NLC gene (13). The onset of symptoms ranges from the second to the eighth decade. Clinical features are characterized by cognitive decline, behavioral issues, recurrent encephalitis-like episodes, parkinsonism, tremors, muscle weakness, neuropathy, seizures, ataxia, and autonomic dysfunction (73). Common autonomic symptoms described are miosis, bladder dysfunction, vomiting, diarrhea, constipation, and orthostatic hypotension. Oculopharyngodistal myopathy and amyotrophic lateral sclerosis phenotypes have been described rarely (73). The disorder is broadly classified into dementia-dominant and muscle weakness-dominant phenotypes based on the earliest and prominent initial symptoms. Dementia presentation appears to be common in late-onset sporadic cases, and familial cases with symptom onset beyond 40 years of age, whereas muscle weakness is the prominent symptom in familial cases with symptom onset earlier than 40 years of age (73). Peripheral neuropathy and muscle involvement with elevated creatine kinase levels are noted in a significant proportion of affected individuals. In the muscle predominant group, symptoms of brain involvement can be delayed as long as two decades (13). Acute encephalitic-like episodes can mimic MELAS and present with focal neurological deficits and altered consciousness (73). Acute clinical and radiological findings in such presentations can be reversible. Longer repeats are associated with an earlier age of symptom onset (73).

MRI brain findings are characterized by symmetric white matter hyperintensities in subcortical, deep, and periventricular white matter in frontal and parietal regions along with volume loss and ventricular dilatation (13, 73). Involvement of the external capsule, splenium, para-vermian region, and middle cerebellar peduncle is commonly seen (Figure 8). Involvement of these structures along with curvilinear DWI hyperintense lesions along the corticomedullary junction is probably a reliable imaging marker for the diagnosis of NIID (73). In the advanced stages, the corticomedullary DWI high-intensity signal appears to extend along the corticomedullary junction, but not into deep white matter (Figure 8). A small proportion of cases might lack diffusion changes. In acute encephalitic-like presentations, focal cortical hyperintensity and edema corresponding to the region of deficit are seen (13).

Accumulation of eosinophilic, hyaline, ubiquitin, and P-62 positive intranuclear inclusions in central and peripheral nervous systems and other organs including the skin is helpful in the pathological diagnosis (73). Clinical, radiological, and skin biopsy findings can significantly overlap with FXTAS, and hence the exclusion of FXTAS by molecular testing is essential (74). Acute encephalitic-like illness needs to be differentiated from viral infections and might show clinical and imaging response to steroids in the short term, though executive dysfunction and other features tend to progress slowly (73).

Fragile X-associated tremor ataxia syndrome (MIM # 300623) is a X-linked hemizygous adult-onset neurodegenerative disorder caused by CGG trinucleotide repeat expansion in the premutation range (55–200 repeats) in the 5′ UTR of the FMR1 gene (75). While full expansion (>200 repeats) leads to methylation-coupled silencing of the gene and results in fragile X syndrome, expansions in the permutation range lead to increased mRNA production and toxicity resulting in intranuclear inclusions in neurons and astrocytes (75). This accumulation causes FXTAS and premature ovarian insufficiency before 40 years of age. Penetrance for FXTAS is not complete, and usually occurs in ~40% of men and 20% of women who carry the premutation allele (75). These individuals are at risk for having children with fragile X syndrome as the trinucleotide repeats could expand to the full mutation range in the next generation. In fact, many symptomatic individuals are diagnosed after a family history of the fragile X syndrome in their children or grandchildren. The absence of family history does not however rule out FXTAS (76).

Symptoms start from the fifth to sixth decade of life, and are characterized by progressive cerebellar ataxia, tremors, cognitive decline, parkinsonism, neuropathy, behavioral issues, and autonomic dysfunction (75). Varying combinations of postural, action, and intention tremors are usually seen. Cognitive involvement is characterized by frontal subcortical dementia with predominant executive deficits. Psychiatric comorbidities such as anxiety, depression, and obsessive–compulsive disorder are common. Eye movement abnormalities and a progressive supranuclear palsy-like phenotype have been described (75). Women with FXTAS tend to have prominent parkinsonism and less frequent tremors when compared to men (76).

MRI brain (Figure 9) reveals generalized cerebral and cerebellar atrophy along with symmetric T2W hyperintensities in the middle cerebellar peduncle, splenium of the corpus callosum, subcortical and periventricular white matter, brain stem, and deep cerebellar white matter (76). Diagnostic criteria have been established with the combination of clinical and imaging features (76, 77). MRI brain findings in a small proportion of affected individuals especially women may lack MCP signal changes. Clinical and radiological features can mimic NIID, as discussed above. Treatment is essentially supportive.

Cerebrotendinous xanthomatosis (MIM# 213700) is an autosomal recessive disorder of bile acid and cholesterol metabolism caused by biallelic pathogenic variants in CYP27A1 that codes for the mitochondrial enzyme sterol 27-hydroxylase (78). Clinical manifestations are characterized by a spectrum of neurological and systemic manifestations. Systemic manifestations predominate early in the disease course with manifestations often starting from childhood with chronic diarrhea, cholestatic jaundice, and cataract. Tendon xanthomas develop in the second to third decade of life. Neurological manifestations usually appear by adolescence to early adulthood with progressive cerebellar ataxia, cognitive decline, epilepsy, spasticity, dystonia, palatal myoclonus, parkinsonism, and neuropsychiatric features (79). A rare spinal presentation called spinal xanthomatosis has been described with slowly progressive myelopathy with corticospinal and long-tract involvement (80). Other systemic manifestations include premature atherosclerosis, osteoporosis, and respiratory insufficiency (78).

Brain imaging reveals symmetric hyperintensity involving the dentate nucleus, corticospinal tracts in pons, and cerebral peduncles, and signal changes in cerebral and deep cerebellar white matter, along diffuse cerebral and cerebellar atrophy (Figure 10). Variable T2 hypointensity and blooming in susceptibility-weighted images in the dentate nucleus are also seen (79). MRI in spinal xanthomatosis usually reveal long segment signal changes along the spinal cord restricted to lateral and dorsal columns (80).

The elevated level of plasma cholestenol is the characteristic metabolic findings. Other lab findings include normal to reduced cholesterol levels, and increased levels of bile alcohols in urine (78). Long-term treatment with chenodeoxycholic acid is effective in reversing the manifestations in most cases. Early identification and timely initiation of treatment help with complete recovery (79).

Hypomyelinating leukodystrophies are clinically and genetically heterogeneous disorders with the common pathology being permanent deficits in CNS myelin formation that result in eventual reduced myelin content (81). Symptoms manifest across all age groups, and adolescence and adult-onset symptoms are not uncommon. Common clinical presentation in late-onset hypomyelinating leukodystrophies is a combination of ataxia and spasticity, with most affected individuals having stable symptoms for decades before experiencing a slow progression of symptoms (81). Episodic worsening with inter-current illness, and improvement to baseline neurological status is known. Cognition is relatively preserved when compared with the extent of motor disability (81). A range of systemic associations such as hypodontia and endocrine abnormalities are known with hypomyelinating leukodystrophies. Advances in molecular testing have broadened the genetic landscape of hypomyelinating leukodystrophies with several implicated genes that code for structural myelin protein, cytoskeletal proteins, and other genes involved in transcription and translation (82). A few disorders that are encountered in adult practice are Pelizaeus-Merzbacher disease (PMD), Pelizaeus-Merzbacher-like disease (PMLD), and POLR3-related disorders (82).

Neuroimaging clinches the diagnosis and is often the initial clue for hypomyelinating leukodystrophies as the clinical symptoms are non-specific and overlap with several other static and degenerative neurologic disorders. Hypomyelination in imaging is characterized by limited myelin content that is depicted as mild T2 hyperintensity and variable (usually iso, hyper, or mild hypo) intensity in T1W images, in contrast to demyelinating disorders that display marked T2 hyperintensity and corresponding T1 hypointensity (81). Apart from the diagnosis of hypomyelination, imaging can provide valuable diagnostic clues based on the regions involved and additional features (81). No definitive treatment options are available at this time, though there are anecdotal reports of stem cell transplants in the early onset and severe cases.

Hereditary cerebral small vessel diseases (CSVD) are a heterogeneous group of disorders that result in progressive white matter changes in imaging, along with multiple lacunar infarcts and microhemorrhages (83). Though the initial manifestation tends to be recurrent transient ischemic attacks or stroke with a step ladder pattern of neurologic decline, clinical features eventually progress to involve cognitive decline, behavioral issues, gait dysfunction, and bladder disturbances (83). Common genetic vascular leukoencephalopathies are cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), COL4A1-related CSVD, cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), SNORD118-related leukoencephalopathy with cysts and calcifications (LCC), FOXC1/FOXF2-related disorders, CTC1-related cerebroretinal microangiopathy with calcifications and cysts, TREX1-related vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations, methylenetetrahydrofolate reductase deficiency, homocystinuria, and Fabry disease (84). Clinical manifestations are heterogenous with symptom onset usually from the third to fourth decade in most disorders. Diagnosis is challenging, as the clinical and imaging findings significantly overlap with sporadic CSVD due to vascular risk factors such as hypertension, hyperlipidemia, and diabetes mellitus which are quite common in the adult population (83).

Common imaging findings are progressive cerebral white matter lesions, multiple lacunes, scattered cerebral microbleeds, dilated perivascular spaces, and cerebral atrophy. Specific imaging findings and systemic associations can help in distinguishing these disorders (85). Though there are no curative treatments available at this time, strict control of modifiable vascular risk factors and usage of antiplatelet therapies when indicated help in slowing down the disease progression to some extent (83).

CLCN2-related leukoencephalopathy (MIM# 615651), also known as leukoencephalopathy with ataxia (LKPAT) is inherited in an autosomal recessive manner and is caused by a defect in water and ion homeostasis in the brain, resulting in intramyelinic edema (91). Clinical features are cerebellar ataxia, spasticity, mild cognitive deficits, and recurrent headaches. Non-neurological manifestations involving eyes with chorioretinopathy and optic neuropathy are common (91). Hearing loss, tinnitus, vertigo, male infertility, and paroxysmal kinesogenic dyskinesia have also been described. Both pediatric and adult-onset symptoms are known, and the clinical course is usually indolent or slowly progressive (91).

MRI brain findings are characteristic, and show signal changes with restricted diffusion involving the posterior limb of the internal capsule and pyramidal tracts in the brain stem, along with the involvement of crus cerebri, central tegmental tract, decussation of the superior cerebellar peduncle, middle cerebellar peduncle, corpus callosum, dentate nucleus, and cerebellar white matter (91). No specific treatment options are available at this time.

Adult polyglucosan body disease (MIM# 615651) is an autosomal recessive adult-onset neurodegenerative disorder due to biallelic pathogenic variants in the GBE1 gene (92). Symptoms occur in the fourth to fifth decade of life with prominent autonomic dysfunction in the form of neurogenic bladder and orthostatic hypotension, gait difficulties with both upper and lower motor neuron involvement, motor sensory axonal neuropathy, and mild executive dysfunction (92). Bladder symptoms are often the initial manifestation, and can antedate gait disturbances even by one to two decades (92). Atypical forms with relapsing-remitting clinical course, subacute presentations, and early-onset liver and neuromuscular disease have been reported (92).

MRI brain reveals hyperintense signal changes in the periventricular, deep, and subcortical supratentorial white matter, pyramidal tract, and medial lemniscus in the pons and medulla, along the cerebellar peduncles, external capsule, and dentate nucleus, as well as a progressive diffuse cerebral, cerebellar, and spinal cord volume loss. Prominent medullary and cervical cord atrophy without any supratentorial white matter changes have been described (93).

Diagnosis is established by skin or sural nerve biopsy demonstrating periodic acid-Schiff positive and diastase-resistant material, and is confirmed by molecular studies that demonstrate biallelic pathogenic variants in GBE1 (92). There are no curative treatment options available at this time.

Vanishing white matter disease (MIM# # 603896, 620312, 620313, 620314, 620315) is an autosomal recessive leukoencephalopathy caused by pathogenic variants in one of the EIF2B1-5 genes (94). Initial presentation in adulthood is not uncommon, with symptom onset described as late as 55 years of age (94). Clinical manifestations in adult-onset presentations are psychiatric symptoms, dementia, motor symptoms including ataxia and spasticity, seizures, and headaches (94). Similar to childhood presentations, varying periods of stability and episodic deterioration with encephalopathy precipitated by febrile infections, minor head trauma, and other stressors are known. Affected females show signs of premature ovarian failure (94).

Neuroimaging demonstrates abnormal T2 hyperintense signal changes involving all of the supratentorial cerebral white matter with progressive rarefaction and cystic degeneration, that typically appears markedly hypodense in FLAIR images similar to that of CSF intensity (94). T1 and FLAIR images show radiating stripes within the areas of rarefaction that represent remaining tissue strands. Variable cerebellar atrophy is seen in late stages (94). Treatment is limited to supportive management and avoidance of trauma and febrile infections.

Neurological manifestations including leukoencephalopathy are one of the prominent features in many of the mitochondrial disorders that are caused by pathogenic variants in both the nuclear genes that encodes mitochondrial proteins, and the mitochondrial genome (95). Clinical manifestations range from early-onset severe leukoencephalopathies to late onset slowly progressive leukodystrophies, along with multisystemic manifestations. Several mitochondrial disorders can have initial symptom onset and presentation in adolescence and adulthood (95). Some of the common mitochondrial disorders encountered in adult neurologic practice are mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), Kearns–Sayre syndrome, Leigh disease, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with ragged red fibers (MERRF), Leber hereditary optic neuropathy, pyruvate dehydrogenase complex deficiency, polymerase gamma (POLG)-related disorders, and various other mitochondrial DNA depletion syndromes (95).

Usual neuroimaging findings are white matter signal changes in supratentorial brain parenchyma sometimes associated with cystic changes and rarefaction, basal ganglia and thalamic signal changes, brain stem involvement, cerebellar white matter changes, and cytotoxic edema during stroke-like episodes (95). MR spectroscopy in the region of abnormal signal changes and sometimes even in the normal-appearing brain regions demonstrating elevated lactate provides additional support to the diagnosis of mitochondrial disorders (95). Although some of the specific clinical manifestations and a corroborative radiologic pattern pinpoint a specific mitochondrial disorder, the manifestations can at times be non-specific, and difficult to diagnose. There should be a high index of suspicion for mitochondrial disorders in the appropriate clinical and imaging context, as this has obvious therapeutic implications, with both use of mitochondrial megavitamins and avoiding some of the medications that are deleterious to mitochondrial function.

Mitochondria rely on several of the nuclear-encoded proteins for the transcriptional and translational regulation of their own housekeeping genes. Mutations in these nuclear-encoded mitochondrial genes, specifically the aminoacyl transfer RNA synthetases are increasingly being recognized as the cause of progressive neurologic disorders, and initial presentation in adulthood is known with this group of disorders. A detailed discussion of the mitochondrial disorders is beyond the scope of this study; however, we discuss two disorders with prominent leukoencephalopathy presentation in adulthood: leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation due to DARS2 variants, and AARS2-related leukodystrophy.

Several other rare leukodystrophies that are encountered in adulthood and are not discussed separately in this article are L2-hydroxyglutaric aciduria due to pathogenic variants in L2HGDH with autosomal recessive inheritance (MIM# # 236792), juvenile or atypical Canavan disease due to biallelic pathogenic variants in ASPA with autosomal recessive inheritance (MIM# 271900), megalencephalic leukoencephalopathy with subcortical cysts due to pathogenic variants in MLC1 with autosomal recessive inheritance (MIM# 604004), AARS1-related leukoencephalopathy due to pathogenic variants in AARS1 with autosomal-dominant inheritance (MIM# 619661), and Sjogren–Larsson syndrome due to pathogenic changes in ALDH3A2 with autosomal recessive inheritance (MIM# 270200).

Despite clinical and radiological overlaps in these disorders, there are several pointers in the prominent neurological symptoms and systemic syndromic associations that would help us to suspect a specific leukodystrophy. These are shown in Tables 2, 3 and would be helpful in daily practice. Broader details including the genes and biochemical testing are shown in Supplementary Table 1.