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 SHORT REPORT 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 examin- ation 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