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Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD) present as adult-onset dementia with motor impairment and epilepsy. They are regarded as distinct diseases. We review data from the literature that support their being a single entity. Apart from a slightly older age at onset, a more rapid course, and more prominent pyramidal tract involvement, familial POLD is clinically similar to HDLS. Moreover, the pathologic hallmarks of the two diseases, axonal spheroids in HDLS and pigmented macrophages in POLD, can be identified in both conditions. This supports HDLS and POLD being referred collectively as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).
Nonmetachromatic or orthochromatic leukodystrophies (OLD) constitute a heterogeneous group of noninflammatory demyelinating disorders.1 Peiffer1,2 distinguished pure forms, special forms, OLD combined with phakomatoses and other disorders, and symptomatic forms. In 1936, Van Bogaert and Nyssen3 described a family with adult-onset OLD associated with pigmented macrophages and other glia (POLD) corresponding to Peiffer's pure forms of OLD. Subsequently, the majority of reported POLD cases have been sporadic; however, no less than eight POLD families have been reported with both recessive and dominant inheritance. Fifty years later in Sweden, Axelsson and colleagues4 described a large family with adult-onset leukoencephalopathy characterized pathologically by the presence of numerous axonal dilations named spheroids. They coined the term hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS).
While POLD and HDLS are regarded as distinct conditions in the literature, recent reappraisal of clinical and pathologic features suggests they may be variants of the same disease.5,6 Herein we review the available literature on POLD and HDLS and provide a critical assessment that supports the hypothesis of a single clinicopathologic entity.
References for this review were identified by searches of PubMed from 1966 until November 2008 with the terms HDLS, POLD, leukodystrophy, leukoencephalopathy, spheroids, and pigmented macrophages. Articles were also identified through searches of the authors' own files, and manual retrieval of articles published before 1966 was performed. Papers in English, French, and German were reviewed.
The core symptoms of HDLS and POLD are behavioral changes, depression, dementia, motor impairment (parkinsonism; spastic hemiparesis, paraparesis, or tetraparesis; ataxia), and epilepsy. However, there is a wide variability in the occurrence and severity of each clinical phenotype. In the following section, we will discuss reported HDLS and POLD families, highlighting pedigrees, symptoms, progression, and treatments.
To date, there are 12 HDLS families reported with detailed clinical and pathologic data (including three familial probands described by Freeman et al.13) (table e-1 on the Neurology® Web site at www.neurology.org).4,5,7-14 In two of them, pathologic criteria were also deemed compatible with familial POLD.5,8 Given HDLS' complex clinical and pathologic presentations and similarity with more common adult-onset white matter diseases, underdiagnosis is likely. An unavailable/unreliable family history or low disease penetrance may also impede its recognition. The distribution of the disease is worldwide, with reported families from Sweden, the Netherlands, the United States, Japan, and Australia. HDLS pedigrees display apparent autosomal dominant disease inheritance. Apart from the original Swedish family in which there were 71 family members and 17 patients over four generations (four patients pathologically verified), reported pedigrees are small, with two to six affected individuals over one to three generations. In the 38 patients for whom this information was available, the age at onset (±SD) was 39 ± 15 years (range, 8–78); disease duration was 9 ± 10 years (range, 1–34) in 31 of them. When removing patients from the over-represented Swedish family, figures were age at onset 40 ± 15 years (range, 15–78; 24 patients) and 5 ± 5 years disease duration (range, 1.5–17; 17 patients). The gender ratio was 0.81 with (58 patients; 26 men) and 0.64 without (41 patients; 16 men) the Swedish family.
Eight families with POLD have been described in the Netherlands, France, Spain, Germany, Japan (two families), Switzerland, and the United States (table e-2). Assessment of published pedigrees shows the disease displays either autosomal dominant15-17 or recessive3,18-21 inheritance. The pedigrees are small, with one to five affected individuals over one to three generations. In the 15 patients for whom this information was available, the age at onset (±SD) was 43 ± 13 years, disease duration was 6 ± 3 years, and gender ratio was 0.7 in 22 patients (13 men).
In HDLS, the initial symptoms are most commonly psychiatric, with depression often being recognized several years before other disease manifestations.5 In the original Swedish family,4 patient II-8 presented with generalized convulsions, reduced spontaneity and initiative, and emotional blunting. Patient III-18 presented with fatigue, apathy, indifference, and lack of initiative, and was diagnosed with depression. Patient III-19 began with personality changes and memory impairment, followed by emotional and intellectual deterioration, whereas patient III-20 presented with right upper limb stiffness and paresthesias, followed by anxiety and gait difficulties. In the other families, four patients manifested depression5,7,9; one had depression and gait impairment5; four had cognitive and behavioral symptoms13,14; two had mental and motor impairment12; one had anxiety, clumsiness, confusion, and stiffness5; four had memory loss7,8,11; one had behavioral changes and gait impairment8; three had parkinsonism7,10; three had hemiparesis10,13; and two had epilepsy.10,12
Neuropsychiatric symptoms have been reported in all identified HDLS families to date (table e-1). The most common psychiatric symptoms are depression and anxiety, described in 70% and 65% of the patients from the Swedish family4 and in several other pedigrees.5,7,9 Depression may be severe, with two patients from the Swedish family committing suicide. Substance abuse such as alcoholism has also been reported.4,12 Disorientation is also a prominent symptom, as are confusion, agitation, irritability, aggressiveness, and memory impairment.4,5,7-14 Most HDLS patients develop dementia, which may be misdiagnosed as Alzheimer disease4,5,7-9,11 or frontotemporal dementia.8 A frontal syndrome, mainly of the apathetic and emotionally blunted type, has been described in several patients,5,7-9,11,13 although a more disinhibited phenotype has also been reported.8,13 Additional symptoms include apraxia5,7,11,13 and mutism.8
Similarly, most familial POLD patients present with neuropsychiatric symptoms (table e-2). Depression and anxiety are particularly common,3,17 as are behavioral changes including disinhibition, aggressiveness, euphoria, and apathy.3,15,18 In the family described by Constantinidis and Wisniewski,15 patients displayed a frontotemporal dementia phenotype consistent with a diagnosis of Pick disease. Psychosis (e.g., paranoid delusions) may occur.3 Diffuse cognitive decline, including memory impairment, but with frontal predominance, eventually occurs in all patients, leading to end-stage dementia.3,16,21
Gait impairment and epilepsy are common neurologic symptoms in both HDLS and familial POLD (tables e-1 and e-2). Gait impairment may stem from parkinsonism, ataxia, pyramidal dysfunction, or a combination of these.5,7,9,10,12 Asymmetric parkinsonian signs exist in some patients with HDLS, mostly rigidity, bradykinesia, and postural instability.5,7,10 In the family described by Baba and colleagues,7 notably asymmetric parkinsonism with apraxia was consistent with corticobasal syndrome and strong family history suggested a diagnosis of frontotemporal dementia–parkinsonism linked to chromosome 17 (FTDP-17). A postural or rest tremor may occur.4,5,7 In contrast, motor impairment in familial POLD is commonly due to prominent pyramidal tract involvement producing spastic paraparesis, tetraparesis, or hemiparesis.3,15-20 An unspecified tremor occurred in one family,15 and an action tremor was noted in another patient.17
Other symptoms in HDLS and familial POLD include ataxia,4,5,7,12,15,17 dysphagia,3,5,10,12,16 and dysarthria,3,5,7,9,10,15 whereas in HDLS families, cortical blindness,13 oral dyskinesia,4 dystonia,4,9 myoclonus,13 apraxia,7,13 and tremor, atrophy, and fasciculations of the tongue5 have been reported. Other symptoms described within POLD families include an afferent pupillary defect,3 apraxia,21 myoclonus,19 and severe headaches.15 Epilepsy has been reported in 7 of the 12 HDLS families and in 5 of the 8 POLD families at variable times during the illness course. In affected patients, generalized tonic-clonic seizures are most common, although partial seizures with7 or without4,16 secondary generalization also have been described.
HDLS and familial POLD typically manifest with neuropsychiatric symptoms, which progress to dementia. In most cases, a frontotemporal phenotype remains predominant with marked personality changes and aberrant behavior, but more diffuse cognitive impairment occurs as well. After a few years, motor dysfunction develops, notably gait impairment. Eventually, most patients with HDLS and patients with POLD become wheelchair-bound or bedridden, with end-stage dementia. In HDLS, the average life expectancy is 9 years and in POLD 6 years. For practical purposes, disease onset was defined as occurrence of either neuropsychiatric or motor symptoms if progressive, excluding a single episode of seizure or depression that would have occurred years before.
Few details have been reported on therapeutic interventions. Depression has been treated with limited benefit using selective serotonin reuptake inhibitors,9 and parkinsonism has responded poorly, or not at all, to carbidopa/levodopa.7
As pointed out in the table, familial POLD and HDLS have very similar clinical presentations. In familial POLD, the age at onset is slightly older, the course of disease is more rapid, and there is more prominent pyramidal tract involvement than in HDLS. Conversely, parkinsonism is more common in HDLS families.
Extensive laboratory evaluations in patients with HDLS, including serum electrolytes; complete blood counts; liver and thyroid function tests; vitamin B12 and folate; vitamin E; cholesterol and triglycerides; amino acids (serum and urine); syphilis and HIV serologies; arylsulfatase A; galactocerebrosidase; sialic acid; α- and β-glucosidase; α- and β-galactosidase; α-mannosidase; α-fucosidase; very long chain fatty acids; antinuclear, antineutrophil cytoplasmic, and antineuronal nuclear antibodies; erythrocyte sedimentation rate; lead and copper; and cortisol, as well as urine organic acids and lactate (blood and CSF), have not revealed any abnormalities.9,10,12
Likewise, in POLD, no abnormality was found in electrolytes, complete blood count, liver and thyroid function tests, vitamin B12, folate, arylsulfatase A and B, glucosidase, galactosidase, mannosidase, fucosidase, xylosidase, nitro-catechol sulfatase A and B, very long chain fatty acids, hexosaminidase A and B, and sphingomyelinase.16,19
CSF studies were normal in HDLS and in POLD, including cell counts, protein, glucose, and oligoclonal bands.4,9,16,19 No studies reported on neuronal markers such as enolase and tau; however, one study found normal CSF levels of protein 14-3-3.9
Cranial CT scans may be normal in the early stages of HDLS,4 but eventually show moderate, frontal-predominant atrophy with enlarged lateral and third ventricles both in HDLS4,5,9-11 and in POLD.16,18,19,21 In HDLS, MRI shows frontal-predominant atrophy with periventricular, callosal, and deep white matter lesions, which may be patchy,12 confluent,7,8,12,13 or diffuse,5,9,12 and have a frontal or frontoparietal predominance (table). Occipital involvement rarely occurs. Our group recently reported serial presymptomatic and symptomatic MRI scans of one patient showing subtle patchy abnormalities (presymptomatic) becoming widespread and confluent (symptomatic).14 Although they are characteristic, MRI features in HDLS are nonspecific and may suggest several alternate diagnoses. Those include white matter diseases such as multiple sclerosis, cerebrovascular diseases (e.g., Binswanger disease, cerebral autosomal dominant arteriopathy with subcortical infarcts), late-onset metachromatic leukodystrophy and Krabbe disease, membranous lipodystrophy, X-linked adrenoleukodystrophy, or chronic exposure to toxic substances (e.g., chemotherapy).12 Most of these conditions can usually be ruled out by appropriate clinical and biologic tests; however, pathologic verification may be required. Magnetic resonance spectroscopy in one study identified an increased choline to creatine ratio in frontal subcortical regions, but with no increase of lactate signal.13 No data are available in the literature on MRI in patients with familial POLD.
SPECT (99mTc-ECD) showed frontoparietal hypoperfusion in one patient with POLD11 and frontotemporal hypoperfusion in one patient with HDLS (tracer not specified in the second study).8 18F-2-fluorodeoxyglusose PET in one patient with HDLS showed generalized hypometabolism, with asymmetric parietal predominance.7 Another study found diffuse frontal and parietal hypometabolism.13
In HDLS, EEGs may be normal,4,7,11 slightly abnormal with intermittent slow activity,5 or show diffuse4,5,10 or paroxysmal slowing.4 Similar normal19 or abnormal18 EEG findings have been reported in patients with POLD, which are sometimes asymmetric16 or with frontal or temporal predominance.15 No clearcut interictal epileptiform patterns were described in either one of the diseases despite epilepsy being a prominent symptom. Nerve conduction studies, visual and somatosensory evoked potentials, and electroretinograms were normal in HDLS4,12 and in POLD.19
Skin and muscle biopsies revealed no red ragged fibers or Lafora bodies in HDLS or in POLD.9,13,19 Atrophy of type II muscle fibers and decreased activity of cytochrome c oxidase, succinate cytochrome c reductase, and NADH-cytochrome c reductase were reported in one study of muscle tissue.13 A sural nerve biopsy showed minimal pathologic changes of an unspecified nature in one patient with POLD.10
The pathologic hallmark of HDLS is widespread loss of myelin sheaths and axonal destruction, numerous axonal spheroids, gliosis, and autofluorescent sudanophilic lipid-laden macrophages (table e-3, figure). Ultrastructural and immunohistochemical studies showed that the spheroids contain phosphorylated neurofilaments, ubiquitin, amyloid precursor protein, and mitochondria.5,9-11,22 Lesions predominate in the frontal lobe, variably in the parietal or temporal lobes, and in the descending pyramidal tracts at the midbrain, brainstem, and spinal cord levels. U-fibers are spared, as are the cortical mantle and the cerebellum. However, abnormalities in the frontal cortex have been described, including neuronal loss10 and ballooned neurons,7 and cerebellar atrophy may occur.4
In familial POLD, there is widespread myelin and axon destruction in a similar distribution, the distinctive feature being the presence of pigmented macrophages and other glia (table e-4, figure).3,16 The sudanophilic pigment is autofluorescent and stains with periodic acid-Schiff, Masson-Fontana coloration, and variably for iron. Ultrastructurally, the pigmented granules are similar to the lipopigment ceroid, with fingerprint, multilamellar, and granular morphology.
As pointed out by Marotti and colleagues,5 there are striking similarities between the POLD and HDLS pathologies. First, in several HDLS families, pigmented macrophages similar to those found in POLD can be identified (figure),13,14 sometimes fulfilling the pathologic criteria for both diseases.5,8 Second, in a study of the original POLD family reported by Van Bogaert and Nyssen, Marotti and colleagues5 demonstrated the presence of numerous axonal spheroids, compatible with HDLS. This is consistent with several POLD families in which pathologic descriptions of axonal dilations correspond morphologically to spheroids.3,5,16,18
In both HDLS and POLD, the mechanism of myelin and axonal damage remains unclear. Brain biopsy results from one of the patients described by Marotti and colleagues5 2.5 years before postmortem examination may be instructive. Abundant spheroids were found on the biopsy, and much less at autopsy, favoring the hypothesis of a primary axonal disease. This view is supported by other authors.12 In POLD, several authors have hypothesized a primary myelin defect,18 and this has recently gained some support by the finding of a defect in the myelin-associated glycoprotein in one family with OLD.23 However, several authors have consistently reported markedly reduced number of oligodendroglial cells, particularly at the periphery of white matter lesions in HDLS and in POLD cases.6,24 These findings suggest a primary oligodendroglialopathy, with secondary myelin and axonal damage. This view is further supported by the reactive rather than dystrophic aspect of axonal spheroids.6
As in other neurodegenerative conditions such as Parkinson disease, the primary biochemical defect in HDLS and POLD may involve oxidative stress.6 First, as pointed out by Ali and colleagues,6 the ceroid found in macrophages and other glia is thought to be an end-product of oxidative damage of various cellular compounds. Second, iron, also found in many HDLS and POLD cases, may increase levels of toxic free radicals, thus leading to cellular energy failure.
In both HDLS and POLD, the frontal predominance of white matter damage is consistent with prominent psychiatric and behavioral symptoms. The common frontotemporal dementia phenotype is also explained by this distribution, and by the associated temporal or parietal involvement. Neuropsychiatric symptoms in HDLS and POLD reflect the disconnection of the temporal, parietal, and occipital cortices from the frontal lobe, mainly affecting associative pathways (discussed in 13). Gait impairment likely has several pathologic correlations. In addition to spastic gait secondary to pyramidal tract lesions, frontal subcortical damage could produce lower body parkinsonism. Ataxia is often present even in patients without cerebellar involvement, which could reflect either minimal cerebellar damage, or diffuse cerebral white matter lesions. As in other leukodystrophies, seizures may be caused by diffuse or patchy white matter lesions.
The genetic cause of HDLS and familial POLD remains unknown, and current families are not large enough for powerful linkage studies. Mutations in one of the five subunits of eukaryotic translation initiation factor eIF2B have been causally implicated in vanishing white matter disease25; however, a mutation in this gene was excluded in one HDLS family, as were mutations in the tau gene (MAPT).7 Similarly, duplications at the chromosome 5q23 locus containing three genes including the LMNB1 gene were identified in families with adult-onset autosomal dominant leukodystrophy.26,27 The discrepant modes of inheritance of HDLS (autosomal dominant) and familial POLD (autosomal dominant or recessive) suggest both diseases are caused by distinct genetic defects. The implication of different genes in one clinicopathologic entity is not uncommon and is exemplified by Parkinson disease due to mutations in the LRRK2 and SNCA genes. Alternatively, the apparent recessive inheritance in some POLD families may reflect reduced penetrance as suggested by the report of sporadic cases (see below).
Several sporadic patients have been described who fulfill clinical and pathologic criteria for HDLS except heritability.28-34 Similarly, most of the patients with POLD reported so far are sporadic.1,19,22,24,35-41 Until the genetic basis for familial aggregation is identified, it remains unknown whether these sporadic cases truly are sporadic or reflect reduced disease penetrance. Conversely, the genetic cause of POLD and HDLS may include the interplay of several genetic factors, some of which may be lacking in sporadic cases.
In a comparative morphologic study of 5 patients with HDLS and 10 patients with POLD, Ali and colleagues6 reported no distinctive pathologic features between the two diseases. In particular, they found spheroids, iron, and ceroid accumulation in the white matter of patients with HDLS and patients with POLD. Further, Marotti and colleagues5 reviewed the literature of reported POLD cases, and found descriptions of axonal spheroids in most of them. This adds to the striking clinical similarities between familial POLD and HDLS discussed in the present review (table). Familial POLD and HDLS have more similarities than differences, and likely belong to the same disease spectrum. In addition, the myelinic, axonal, or oligodendroglial origin of white matter disruption remains contentious, thereby complicating the distinction between leukodystrophy (POLD) and leukoencephalopathy (HDLS). As suggested before, evidence supports HDLS and POLD being collectively referred to as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).6
There is compelling evidence that HDLS and familial POLD belong to the same disease spectrum. Grouping them together as ALSP may foster their heightened recognition as it is conceivable that they are underrecognized. In so doing, identifying their genetic causes may be enhanced.
The authors thank Dr. Chadwick W. Christine for providing clinical material.
Address correspondence and reprint requests to Dr. Zbigniew K. Wszolek, Department of Neurology, Cannaday Building 2E, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224 wszolek.zbigniew/at/mayo.edu.
Supplemental data at www.neurology.org.
C.W. is supported by the Swiss National Science Foundation (PASMP3-123268/1) and the Swiss Parkinson Foundation. Z.K.W. and D.W.D. are supported by the Morris K. Udall NIH/National Institute of Neurological Disorders and Stroke Parkinson Disease Center of Excellence Grant awarded to the Mayo Clinic Jacksonville P50NS40256, by NIH/NIA P01AG017216 and NIH/NIA R01AG015866 grants, and by the Pacific Alzheimer Research Foundation Centre (PARF) C06-01 grant.
Disclosure: The authors report no disclosures.
Received December 16, 2008. Accepted in final form February 27, 2009.