A Unique Familial Leukodystrophy with Adult Onset Dementia and Abnormal Glycolipid Storage: a New Lysosomal Disease?

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J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.2.251 on 1 August 1998. Downloaded from J Neurol Neurosurg Psychiatry 1998;65:251–254 251

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A unique familial leukodystrophy with adult onset dementia and abnormal glycolipid storage: a new lysosomal disease?

David K Simon, Michael L Rodriguez, Matthew P Frosch, Elizabeth J Quackenbush, Steven K Feske, Marvin R Natowicz

Abstract tia, particularly in younger patients, necessi- Two adult siblings with early onset demen- tates an aggressive search for potentially treat- tia are described. At presentation, in their able aetiologies. Although eVective treatments early 30s, they showed poor judgment and for most leukodystrophies remain a hope for disinhibition. A progressive dementia en- the future, progress towards this goal will sued over several years. Brain MRI dis- require the appropriate classification of pa- closed diVusely increased T2 signal in the tients. In addition, the identification of an aeti- cerebral white matter, suggestive of a leu- ology for a patient’s clinical condition has kodystrophy. Numerous lysosomal en- important implications for others in the family zyme assays including leucocyte who may be at risk for developing symptoms arylsulphatase A and galactocerebrosi- and who may benefit from genetic counselling dase activities, plasma and fibroblast very for family planning. long chain fatty acid concentrations, and We report here a brother and sister with urinary sulphatide concentrations were onset in their 30s of a progressive dementia normal, as were CSF analyses. A brain associated with diVuse changes in cerebral biopsy disclosed periodic acid SchiV white matter. The biochemical and pathologi- (PAS) and Sudan black positive material cal changes identified in these patients do not in perivascular macrophages which, by conform to the patterns reported for any of the electron microscopy, consisted of stacks of known leukodystrophies. straight or curvilinear paired membranes within angulate lysosomes, indicative of abnormal glycolipid accumulation. The http://jnnp.bmj.com/ combination of clinical, radiological, bio- Case 1 chemical, and pathological features of this Patient 1 was a 37 year old man with a six year degenerative disease is not consistent with history of progressive cognitive decline and Brigham and Women’s that of any of the known leukodystrophies Hospital, Boston, MA, poor judgment as manifested by inappropriate USA or lysosomal storage disorders. These dressing for the weather and urination in pub- D K Simon findings suggest a previously undescribed lic. He was institutionalised in a psychiatric M L Rodriguez familial glycolipid storage disorder caus- facility at the age of 33. M P Frosch ing an adult onset leukodystrophy and He was born after a full term gestation and on September 28, 2021 by guest. Protected copyright. S K Feske presenting with behavioural symptoms had normal developmental milestones and no that mimic a psychiatric disorder. Shriver Center and evidence of psychiatric or neurological disease (J Neurol Neurosurg Psychiatry 1998;65:251–254) Massachusetts General before the age of 31. He worked as a welder Hospital, Boston, MA, Keywords: leukodystrophy; dementia; lysosomal until the age of 32 and was divorced at that age. USA disorder The family history was notable for a similarly M R Natowicz aVected older sister (case 2). The parents, two Children’s Hospital brothers (30 and 36 years old), and a younger and Center for Blood Although most inherited leukodystrophies are sister (24 years old) were reported to be Research, Boston, MA, paediatric disorders, adult onset presentations clinically normal, as were the 4 year old son of USA occur in some, including X linked adrenoleu- patient 1 and the 18 year old son of his affected E J Quackenbush kodystrophy, metachromatic leukodystrophy, sister. The paternal grandmother was reported Correspondence to: Krabbe’s disease, orthochromatic leukodystro- to have Parkinson’s disease. There was no Dr David K Simon, phy, polycystic lipomembranous osteodyspla- known consanguinity. Department of Neurology, sia with sclerosing leukoencephalopathy, and Physical examination at the age of 34 Brigham and Women’s 12 disclosed a non-dysmorphic person whose Hospital, 75 Francis Street, Alexander’s disease. Each is associated with Boston, MA 02115, USA. characteristic clinical and pathological features general medical examination was unremark- and, in the case of X linked adrenoleukodystro- able. Mental status examination showed inat- Received 14 July 1997 and in phy, metachromatic leukodystrophy, and Krab- tention. There was paucity of speech and revised form 15 December 1997 be’s disease, with specific biochemical and limited thought content, but language and Accepted 14 January 1998 molecular abnormalities. The onset of demen- recent memory were intact. AVect was blunted. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.2.251 on 1 August 1998. Downloaded from 252 Simon, Rodriguez, Frosch, et al

Electron micrograph of abnormal membrane proﬁles present within a macrophage from the brain biopsy of patient 1. The material is predominantly contained within membrane bound compartments. Original magniﬁcation ×19 000.

Motor restlessness was apparent. Palmar grasp larger angulate lysosomes, these membranes reflexes were absent. A slight postural tremor of were admixed with coarsely clumped, variably the upper limbs was present. Neurological osmophilic material resembling lipofuscin, as examination was otherwise unremarkable in- well as more uniformly granular osmophilic cluding normal extraocular movements and material. Scattered cortical neurons contained deep tendon reflexes. At this time, an EEG and coarse, irregular, densely osmophilic material EMG with nerve conduction studies were nor- and round lipid droplets (lipofuscin). Within mal. T2 weighted MRI of the brain disclosed some of the clumps, straight or slightly curved diVusely increased signal involving much of the acicular clefts and rare paired membrane white matter of the cerebral hemispheres and profiles were identified. brainstem. At the age of 36, physical examination disclosed inattention and marked frontal Case 2

release signs including poor word list genera- Patient 2, the 38 year old sister of patient 1, had http://jnnp.bmj.com/ tion, diYculty with Luria sequences, palmar a 5 year history of cocaine and alcohol misuse grasp reflexes, and a visually evoked sucking and progressive cognitive decline. She was the reflex. Apraxia was notably absent. There was product of a full term gestation and had normal marked motor restlessness. Pendular nystag- developmental milestones and no evidence of mus and diVuse hyperreflexia were present. By psychiatric or neurological disease before the the age of 37 he was non-verbal and had absent age of 33. She graduated from high school and deep tendon reflexes in the lower limbs. worked as a cashier and hairdresser until the

Laboratory evaluation is summarised as fol- age of 33. Shortly thereafter, her personality on September 28, 2021 by guest. Protected copyright. lows: a low TSH was due to Graves’ disease, gradually changed. She became disinhibited, which was treated with propylthiouracil. A manifested by urination in public and two right frontal brain biopsy showed slight patchy arrests for indecent exposure. Her family noted pallor of myelin, mild gliosis, and occasional her to have poor judgment, impaired short groups of perivascular macrophages in the term memory, and incontinence of urine and subcortical white matter containing periodic faeces. There were several psychiatric admis- acid SchiV (PAS) positive and Sudan black sions between the ages of 34 and 38, including positive but non-metachromatic granules con- at least one for alcohol and cocaine misuse. She sistent with glycolipid. Axons within the white was placed in a neuropsychiatric facility at the matter were irregularly swollen and rare axonal age of 38. spheroids were noted. The cerebral cortex was Physical examination at the age of 38 normal without evidence of abnormal storage disclosed no dysmorphic features and a normal material or inflammation. Electron microscopi- general physical examination. Mental status cal analysis showed perivascular macrophages examination showed inattention, perseveration, containing numerous angulate lysosomes filled and emotional lability with impaired executive with stacks of straight or curvilinear, non- functions but intact language. Palmar grasp branching paired membrane profiles (figure). reflexes were absent. Neurological examination Each membrane pair consisted of two roughly was otherwise unremarkable including normal 2.5 nm thick membranes separated by a articulation and intact extraocular movements uniform 2.5–3.0 nm electron lucent space. In without nystagmus. Formal neuropsychiatric J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.2.251 on 1 August 1998. Downloaded from A unique familial leukodystrophy with adult onset dementia and abnormal glycolipid storage 253

testing at the age of 38, 6 months after institu- analysis using PAS and Sudan black stains tionalisation, disclosed progression of cognitive indicated that the stored substrate(s) was deficits. T2 weighted MRI of the brain glycolipid. disclosed diVusely increased signal intensity Pathological storage within angulate lyso- involving much of the white matter in the somes is noted in many conditions, both cerebral hemispheres and brainstem, similar in genetic and non-genetic.3 In general, angulate distribution and severity to the MRI findings in lysosomes develop whenever macrophages ac- patient 1. cumulate material, usually lipid, that imparts an angulate shape to the lysosomes in which it is stored. This is noted to occur by either of two Laboratory investigations mechanisms: (1) pathological storage of mate- Serum studies with normal results in both rial derived from endocytosed cells or cell patients included quantitative serum amino membranes that accumulates because the deg- acids, very long chain fatty acid concentrations, radative capacity of the otherwise normal mac- beta-N-acetylhexosaminidases A and B, rophage is exceeded, or (2) pathological â-mannosidase (tested in patient 1 only), storage because of a primary metabolic defi- á-fucosidase, á-mannosidase, and lactate. Nor- ciency, usually in lipid catabolism.3 mal leucocyte studies included arylsulphatase The occurrence of this leukodystrophy in A, galactocerebrosidase, á-N-acetylgalacto- siblings with normal parents constitutes a saminidase, ceramidase, â-galactosidase, strong argument that the underlying pathoge- á-mannosidase, and á-galactosidase. Studies in netic process is genetic and likely autosomal fibroblasts in both patients disclosed normal recessive. However, we are unaware of any very long chain fatty acid (VLCFA) concentra- described genetic disorder that is consistent tions, plasmalogen synthesis, phytanic acid with the entirety of findings noted here. The oxidation, arylsulphatase A, cerebroside sul- clinical and radiological findings in our patients phatase, sulphatide loading test, and suggested the possibility of metachromatic leu- â-glucosidase. Normal urine studies included kodystrophy, which can present in adults with sulphatides, neutral oligosaccharides, sialic dementia.4 However, neither patient had defi- acid-containing oligosaccharides, free sialic cient arylsulphatase A activities. In addition, acid, and bile acids (in patient 2 only). Analysis normal urinary sulphatide concentrations and of CSF showed no leucocytes in patient 1, 3 a normal fibroblast sulphatide loading study lymphocytes in patient 2. Protein and glucose ruled out all known forms of metachromatic in CSF were normal in both patients; CSF lac- leukodystrophy. The lack of metachromatic tate and quantitative amino acids were normal staining and the ultrastructural findings also in patient 2. Leucocyte karyotype was normal are inconsistent with a diagnosis of metachro- in patient 1 (46 XY). Leucocyte and fibroblast matic leukodystrophy. karyotypes in patient 2 were normal (46, XX). X linked adrenoleukodystrophy is a peroxi- Light and electron microscopical analysis of somal disorder of very long chain fatty acid skin biopsies disclosed no abnormalities in (VLCFA) catabolism.5 The adult onset form of either patient. A cortrosyn stimulation test was X linked adrenoleukodystrophy, adrenomy- normal in patient 1. TSH was low in patient 1 eloneuropathy, usually presents in young adult (<0.3 mU/l, normal 0.5–5), with a high T4 men with spastic paraparesis. Rare cases of http://jnnp.bmj.com/ (19 µg/l, normal 0.8–2.3) and borderline T3 patients with adult onset X linked adrenoleu- uptake (41%, normal 80–200). TSH was kodystrophy with progressive dementia or psy- normal in patient 2. Other studies that were chosis but without signs of spinal cord involve- normal (tested in one or both patients) ment have been reported.56The ultrastructural included B12, folate, ceruloplasmin, copper, features of the macrophage inclusions in the HIV, rapid plasma reagin test, and erythrocyte brain biopsy of patient 1 are similar to those sedimentation rate. described in X linked adrenoleukodystrophy.37

Cytoplasmic inclusions are found in many cell on September 28, 2021 by guest. Protected copyright. Discussion types in the disease, but in macrophages, the We report here two siblings with a progressive inclusions are located within angulate lyso- adult onset dementia associated with a leuko- somes. However, the normal serum and dystrophy by MRI and a brain biopsy disclos- fibroblast VLCFA analyses rule out a diagnosis ing membrane enclosed glycolipid inclusions of X linked adrenoleukodystrophy.8–10 In addi- within perivascular macrophages. Extensive tion, the disease is X linked, and whereas laboratory investigations did not disclose bio- female heterozygotes can be symptomatic,11 chemical defects associated with any of the The phenotype and radiological findings of known leukodystrophies. To our knowledge, patient 2 would be unusual for that disorder. the combination of clinical, pathological, and Thyroid disease has been incidentally associ- biochemical findings in these siblings has not ated with X linked adrenoleukodystrophy,12 but previously been reported. it is not a common feature. However, our A central issue in these patients is whether patients were discordant for thyroid disease the disorder in question is a primary genetic and the neurological symptoms in patient 1 lysosomal storage disease versus a secondary continued to progress despite successful accumulation of substrate within lysosomes of therapy for hyperthyroidism. Therefore, thy- perivascular CNS macrophages. Electron mi- roid abnormalities do not account for the leu- croscopy of those cells disclosed a pathological kodystrophy in our patients. accumulation of straight and curvilinear mem- Other inherited leukodystrophies that can branes within angulate lysosomes. Histological present in adults, such as Krabbe’s disease, J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.2.251 on 1 August 1998. Downloaded from 254 Simon, Rodriguez, Frosch, et al

orthochromatic leukodystrophy, polycystic not noted in demyelinating disorders of the lipomembranous osteodysplasia with sclero- CNS. The intralysosomal pathology is likely sing leukoencephalopathy (membranous due to a new genetic lysosomal enzyme lipodystrophy), and Alexander’s disease do not deficiency disorder associated with defective present with isolated dementia.213The normal glycolipid catabolism. However, an alternative galactocerebrosidase activity in both patients explanation, that the lysosomal storage is a sec- also rules out Krabbe’s disease. In addition, the ondarily produced pathology caused by a non- brain biopsy of patient 1 did not show the lysosomal genetic abnormality cannot be ex- characteristic features associated with these cluded. Identification of the substrate(s) stored disorders such as the globoid cells of Krabbe’s in the CNS macrophages may be helpful in disease or the Rosenthal fibres of Alexander’s diVerentiating between these possibilities and disease. in establishing the primary biochemical lesion. Chronic solvent vapour inhalation can cause a demyelinating disorder in the CNS associated We thank Dr Hugo W Moser for helpful discussions and assist- with inclusions within membranous vesicles in ance with the fibroblast very long chain fatty acid assay. macrophages similar to those seen in the brain 14 1 Calandriello L, Matteucci C, Bertini E, et al. Biopsy diagno- biopsy of patient 1. However, neither patient sis of a case of adult onset orthochromatic leukodystrophy. had a history of solvent vapour misuse. The Clinical and brain biopsy findings. Ital J Neurol Sci 1992;13:787–92. continued progression of the disease in both 2 Coker SB. The diagnosis of childhood neurodegenerative patients while in institutional care, when they disorders presenting as dementia in adults. Neurology 1991;41:794–8 . likely do not have access to drugs of misuse, 3 Dingemans KP, Mooi WJ, van den Bergh Weerman MA. also argues against solvent vapour misuse as a Angulate lysosomes. Ultrastruct Pathol 1983;5:113–22. 4 Kolodny EH, Fluharty AL. Metachromatic leukodystrophy factor in these patients. and multiple sulfatase deficiency: sulfatide lipidosis. In: The current patients are also distinct from Scriver CR, Sly WS, Valle D, eds. The metabolic and molecular basis of inherited diseases, 7th ed. Vol 1. New York: 1995: previous reports of patients with unique 2693–739. leukodystrophies. For example, Axelsson et al15 5 Moser HW, Smith KD, Moser AB. X-linked adrenoleukodystrophy. In: Scriver CR, Sly WS, Valle D, eds. The metabolic reported a familial hereditary leukoencepha- and molecular basis of inherited diseases, 7th ed. Vol 1. New lopathy presenting with dementia in adults. York: 1995:2325–49. 6 Esiri MM, Hyman NM, Horton WL, et al. However, the pattern of inheritance was Adrenoleukodystrophy: clinical, pathological, and bio- autosomal dominant and axonal spheroids was chemical findings in two brothers with the onset of cerebral disease in adult life. Neuropathol Appl Neurobiol 1984;10: a prominent histopathological feature, thus 429. distinguishing their patients from those pre- 7 Ghatak NR, Nuchlin D, Peris M, et al. Morphology and dis- 16 tribution of cytoplasmic inclusions in adrenoleukodystro- sented here. Yates et al described a patient phy. J Neurol Sci 1983;50:391. with a leukodystrophy and adult onset demen- 8 Moser HW, Moser AE, Trojak JE, et al. Identification of female carriers of adrenoleukodystrophy. J Pediatr 1983; tia with motor and cranial nerve deficits, but 103:54–9. the striking cholesterol ester accumulation seen 9 O’Neill BP, Moser HW, Saxena KM, et al. Adrenoleukodystrophy: clinical and biochemical manifes- in that patient was absent in ours. tations in carriers. Neurology 1984;34:798–801. We have identified a unique familial leuko- 10 Kennedy CR, Allen JT, Fensom AH, et al. X-linked adrenoleukodystrophy with non-diagnostic plasma very long chain dystrophy presenting as dementia in adults. A fatty acids. J Neurol Neurosurg Psychiatry 1994;57:759–61. brain biopsy disclosed abnormal accumulation 11 Edwin D, Speedie L, Naidu S, et al. Cognitive impairment in adult-onset adrenoleukodystrophy. Mol Chem Neu- of glycolipid within macrophages. To the best ropathol 1990;12:167–76.

of our knowledge, the constellation of clinical, 12 Dumic M, Gubarev N, Sikic N, et al. Sparse hair and multi- http://jnnp.bmj.com/ ple endocrine disorders in two women heterozygous for radiographic, biochemical, and pathological adrenoleukodystrophy. Am J Med Genet 1992;43:829–32. data of our patients does not correspond to any 13 Gray F, Destee A, Bourre JM, et al. Pigmentary type of orthochromatic leukodystrophy (OLD): a new case with described genetic or non-genetic leukodystro- ultrastructural and biochemical study. J Neuropathol Exp phy. Increased turnover of myelin membrane Neurol 1987;46:585–96. 14 Kornfeld M, Moser AB, Moser HW, et al. Solvent vapor and resultant intralysosomal accumulation of abuse leukodystrophy. Comparison to adrenoleukodystro- glycolipid within CNS macrophages as a result phy. J Neuropathol Exp Neurol 1994;53:389–98. of demyelination theoretically might explain 15 Axelsson R, Roytta M, Sourander P, et al. Hereditary diffuse leucoencephalopathy with spheroids. Acta Psychiatr Scand

the histological and ultrastructural ﬁndings 1984;69:7–59. on September 28, 2021 by guest. Protected copyright. 16 Yates AJ, Kishimoto Y, Richard C, et al. Sudanophillic leu- reported here. However, this is an unlikely kodystrophy with large amounts of cholesterol ester. explanation as similar pathological ﬁndings are Neurochemical Pathology 1983;1:103–23.