Downloaded from jnnp.bmj.com on September 2, 2014 - Published by group.bmj.com Multiple sclerosis REVIEW A practical approach to diagnosing adult onset leukodystrophies Editor’s choice Scan to access more free content R M Ahmed,1 E Murphy,2 I Davagnanam,3 M Parton,4 J M Schott,1 C J Mummery,1 J D Rohrer,1 R H Lachmann,2 H Houlden,5 N C Fox,1 J Chataway6 ▸ Additional material is INTRODUCTION CASE STUDY published online only. To view The term leukodystrophy refers to a group of condi- A middle aged patient presented to an MS clinic please visit the journal online tions that are inherited and involve the progressive with a 2-year history of progressive gait and cogni- (http://dx.doi.org/10.1136/ 1 jnnp-2013-305888). destruction or loss of previously acquired myelin. tive difficulties. Two years earlier, the patient had The most commonly reported of these disorders noted dragging of the right leg, difficulty control- For numbered affiliations see end of article. have a metabolic origin and are associated with ling the leg and had had several falls. One year abnormalities on specialist biochemical testing. prior, clumsiness and weakness in the right hand Correspondence to Recently, a number of conditions caused by genes had been noted, as well as word finding difficulties, Dr J Chataway, Department of coding for proteins not directly involved in meta- slowness of thought, problems with episodic Neuroinflammation, Queen Square Multiple Sclerosis Centre, bolic pathways and for which the diagnosis relies memory and that their writing and spelling had National Hospital for Neurology directly on gene analysis have also been described. deteriorated. The patient had a past history of sciat- & Neurosurgery and University In clinical practice, distinguishing ‘classical’ inher- ica and long standing depression. The patient’s College London Institute of ited leukodystrophies from other causes of white mother had died at 65 years of age after a 5-year Neurology, Queen Square, matter disease, including vascular and inflammatory decline in gait and cognitive function, with MRI London WC1N 3BG, UK; [email protected] disorders, may not always be straightforward. brain showing generalised cerebral atrophy and Although individually rare, with no single condi- patchy signal change in the peri-ventricular white Received 19 September 2013 tion having a prevalence of >1 in 20 000, the matter. The mother had been given a diagnosis of Revised 4 November 2013 reported prevalence of adult onset leukodystrophies vascular dementia. There was no other family Accepted 19 November 2013 Published Online First is rising. This is likely to be related to the increased history of neurological or psychiatric illness. 19 December 2013 use of brain MRI and new genetic insights. On examination, the patient had broken smooth Collectively their incidence may rival that of mul- pursuit eye movements and hypometric saccades. tiple sclerosis (MS).2 Nonetheless, the rarity of The cranial nerves were intact. The upper limb each condition and the wide differential means that examination was normal. The lower limb examin- diagnosis can be challenging and most clinicians ation showed increased tone and power of 4/5 on will lack experience in the area. Currently, a signifi- the right, with a pyramidal pattern of weakness. cant proportion of individuals may remain without The reflexes were brisk throughout, with equivocal a precise diagnosis despite intensive investigations. plantar responses. The gait was apraxic. On cogni- Much has been written in the paediatric litera- tive testing she scored 22/30 on the Mini-Mental ture about leukodystrophies,3 but the adult neur- State Examination. On neuropsychometric testing, ologist, with a new case, is often left with an there was evidence for generalised cognitive decline extensive and detailed table of rare disorders to with marked impairments on tests sensitive to consider, without an obvious diagnostic pathway to frontal and parietal lobe functions. follow. In addition, leukodystrophies that classically MRI brain (see online supplementary figure S1) present in infancy or childhood may have a very showed extensive white matter change predomin- different or attenuated clinical presentation in antly affecting the frontal lobes with involvement adulthood, making diagnostic features less familiar. and thinning of the corpus callosum. In this review, taking a clinical case as a starting point, we address: ▸ the most commonly presenting leukodystrophies in adults What is the differential diagnosis and which ▸ their clinical presentations initial investigations should be performed? ▸ MRI patterns for specific leukodystrophies With this symptom complex and widespread white ▸ how to investigate leukodystrophies in an adult matter change on MRI, there are a number of ▸ current and future treatment possibilities. acquired conditions that need to be excluded before Table 1 summarises the most frequent of the an inherited leukodystrophy is considered. These inherited leukodystrophies that have been reported include inflammatory, autoimmune, infectious, neo- to present in adulthood (age of onset of plastic, metabolic, drug and toxic causes. Suggested >16 years). This list is not exhaustive and almost initial (Round 1) investigations are outlined in To cite: Ahmed RM, — Murphy E, Davagnanam I, certainly underestimates the true numbers with online supplementary table S1. A very rapid onset et al. J Neurol Neurosurg more widespread access to genetic testing it is likely and progression over months is much more likely Psychiatry 2014;85: that the list of potential diagnoses and actual preva- to be acquired than genetic, though cerebral adre- – 770 781. lences will continue to increase. noleukodystrophy (ALD) can present abruptly. 770 Ahmed RM, et al. J Neurol Neurosurg Psychiatry 2014;85:770–781. doi:10.1136/jnnp-2013-305888 Ahmed RM, Table 1 Leukodystrophies presenting in adulthood Disorder Age of onset Prevalence of adult disease Ethnic predilection Inheritance Useful investigation(s) Gene(s) et al X linked adrenoleukodystrophy Childhood to adulthood Up to 40/million, adult cerebral ALD X linked. Female Very long chain fatty acid levels ABCD1 . – J Neurol Neurosurg Psychiatry adrenomyeloneuropathy (ALD/ accounts for 5% of cases; 15% 20% of carriers can develop AMN)45 heterozygote women are symptomatic AMN/spastic paraparesis Cerebral autosomal dominant Migraine: mean 30 years 10–40/million AD and sporadic Electron microscopy of skin biopsy NOTCH3 arteriopathy with subcortical infarcts (range 6–48 years). and leukoencephalopathy Ischaemic events: mean Downloaded from (CADASIL)67* 50 years (range 20– 70 years) Globoid cell leukodystrophy (Krabbe Up to 60 years 10/million, 10% adult onset AR Galactocerebrosidase (GALC) enzyme activity GALC; disease)89 (leukocytes/fibroblasts) PSAP 2014; Metachromatic leukodystrophy Up to 70 years 2/million, 20% adult onset AR Arylsulfatase A (ARSA) enzyme activity ARSA; (MLD)10 (leukocytes/fibroblasts)† PSAP 85 jnnp.bmj.com :770 Cerebrotendinous xanthomatosis Juvenile to adulthood 2/million AR Sterol profile. Urine bile alcohols CYP27A1 (CTX)811 – 781. doi:10.1136/jnnp-2013-305888– 771 Mitochondrial disorders12 14* Childhood and adulthood Total prevalence 100–165/million, Maternal, AD, AR Lactate (blood/CSF). Mitochondrial respiratory Various —any age prevalence of leukoencephalopathy in chain enzyme activity adults is not known, paediatric literature suggests it is common onSeptember2,2014-Publishedby Hereditary diffuse Mean 40 years (range 15– 52 cases described in literature, AD and sporadic Characteristic brain biopsy findings (now CSFR1 leukoencephalopathy with 78 years) incidence increasing with recent superseded by molecular genetic testing) neuroaxonal spheroids (HDLS)15 discovery of CSF1R gene Adult polyglucosan body disease 40–60 years 47 cases Ashkenazi Jewish AR Sural nerve biopsy. Glycogen brancher enzyme GBE1 (APBD)16 (GBE) activity (fibroblasts) Alexander disease17 12–62 years 36 cases AD and sporadic Characteristic brain biopsy findings (now GFAP superseded by molecular genetic testing) Adult onset autosomal dominant 30–50 years Unknown: at least 27 cases reported in AD LMNB1 leukodystrophy (ADLD)18 19 literature Vanishing white matter disease Mean 30 years (range 16– 177 cases in total, 25 with onset AR eIF2B 1–5 (VWM)20 62 years) >16 years Cerebral autosomal recessive 20–50 years Unknown, thought to be rare, 50 cases Most reported cases in Japan AR On brain pathology, CARASIL is characterised by HTRA1 arteriopathy with subcortical infarcts described thus far and China intense arteriolosclerosis without the deposition and leukoencephalopathy of granular osmiophilic materials in small arteries group.bmj.com (CARASIL)21* and arterioles that is seen in CADASIL Hexosaminidase A (HEX A) deficiency 20–40 years Small case series 64% Jewish origin AR β-HEX A enzymatic activity (leukocytes) HEXA (GM2 gangliosidosis, adult onset Tay–Sachs disease)22 Megalencephalic 6 months–50 years 11 cases aged >20 years Asian-Indian, Turkish AR MLC1; leukoencephalopathy with subcortical HEPACAM cysts (MLC)23 Multiple sclerosis MTHFR deficiency24 Any age Limited case reports AR Plasma amino acid profile MTHFR α-Mannosidosis25 Adolescence, but severe Limited case reports AR Urine oligosaccharides. Vacuolated lymphocytes. MAN2B1 ataxia 30–40 years α-Mannosidase enzyme activity (leukocytes) Mucolipidosis type IV826 Usually infant childhood, 1 Late onset reported due to attenuated Ashkenazi Jewish AR MCOLN1 case onset 16 years14