Download to read offline
More Related Content
Similar to Adulthood leukodystrophies .pptx
Adulthood leukodystrophies .pptx
- 1. ADULTHOOD LEUKODYSTROPHIES Dr Miny SusanAbraham DM Neurology Resident
- 2. Introduction • Leukodystrophies areinherited disorders that affect the cerebral white matter with or without peripheral nervous system involvement ; with heterogeneous genetic background, considerable phenotypic variability and disease onset at all ages. • Cells involved in the axon–glia unit, such as oligodendrocytes, astrocytes, ependymal cells and microglia, are specifically affected. • Alterations to these non-neuronal cells lead to myelin sheath — and subsequently axonal — pathology.
- 3. History • Pelizaeus andMerzbacher separately described the familial occurrence of a chronic progressive ‘diffuse sclerosis’ (as opposed to the already recognized ‘multiple sclerosis’) with lack of myelin and sclerotic hardening of the white matter ; century back. • The term “leukodystrophy” (leuko, white and dystrophy, wasting) was used for the first time in 1928 in the context of metachromatic leukodystrophy and coined to define hereditary, progressive diseases characterized by white matter degeneration.
- 4. • Some usesthe term “leukoencephalopathy” to define all disorders that affect exclusively or predominantly the brain white matter. • Currently used where pathology does not primarily affect glia , conditions include systemic inborn errors of metabolism and primary neuronal disorders such as neuronal ceroid lipofuscinoses . • Leukodystrophies are currently defined as all genetically determined disorders primarily affecting central nervous system white matter, irrespective of the structural white matter component involved, the molecular process affected and the disease course.
- 5. Leukodystrophies that canpresent with adult onset • Pol-III-related disorders (4H syndrome (hypomyelination, hypodontia, and hypogonadotropic hypogonadism) • X linked adrenoleukodystrophy(X-ALD) • Adult-onset leukodystrophy with neuroaxonal spheroids and pigmented glia (including hereditary diffuse leukoencephalopathy with spheroids (HDLS), and pigmentary type of orthochromatic leukodystrophy with pigmented glia (POLD) • Alexander disease (AxD) • Autosomal-dominant leukodystrophy with autonomic disease (ADLD) • Cerebrotendinous xanthomatosis (CTX) • ClC-2 related leukoencephalopathy with intramyelinic oedema • eIF2B-related disorder (vanishing white- matter disease or childhood-onset ataxia and cerebral hypomyelination (CACH)
- 6. • Globoid cellleukodystrophy (Krabbe) • Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) • Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL) • Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) • Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) • Metachromatic leukodystrophy and its biochemical variants • Peroxisomal biogenesis disorders • Polyglucosan body disease (PGBD) • RNAse T2-deficient leukoencephalopathy
- 7. Classification • Hypomyelinating andDysmyelinating types Hypomyelinating leukodystrophy with atrophy of basal ganglia and cerebellum (HLD6), Pelizaeus–Merzbacher disease (HLD1) Pelizaeus– Merzbacher-like disease (HLD2) Pol-III-related disorders (HLD7 and HLD8) Rest belong to dysmyelinating phenotype
- 8. Based on pathologicalmechanism • Inborn Errors of Metabolism – X-ALD,MLD ,Krabbe,CTX ,Canavan,Polyglucosan disease. • Disorders of RNA/DNA Transcription/Translation -Aicardi-Goutières syndrome,Pol III related disorders ,HBSL ,LBSL • Genes Related to Proteins Critical for Myelin Development – pelizieus – Merzbachers • Cytoskeletal. – Alexander , ADLD • Myelin Water Maintenance – Megalencephalic leukoencephalopathy with subcortical cysts, • Mechanism Not Yet Elucidated - HDLS
- 9. Based on cellof origin • Myelin disorders • Astrocytopathies – alexander ,Megalencephalic leukoencephalopathy with subcortical cysts,s • Microgliopathies - hereditary diffuse leukoencephalopathy with spheroids (HDLS), and pigmentary type of orthochromatic leukodystrophy with pigmented glia (POLD). • Leukoaxonapathies – Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL) , Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL ). • Leukovasculopathies
- 10. • Around 30distinct clinical syndromes may manifest in adulthood. • Leukodystrophies rarely show precise genotype–phenotype correlation, and the same gene defect might cause both childhood and adulthood phenotypes in the same family, as observed in X linked ‑ adrenoleukodystrophy (X ALD), for example ‑ • Adrenomyeloneuropathy(AMN) phenotype of X-ALD, or adult polyglucosan body disease (APBD), progress slowly over years or even decades. • Metachromatic leukodystrophy(MLD),Krabbe,cerebral presentation of X-ALD – Rapid deterioration. • Megalencephalic leukoencephalopathy with subcortical cysts (MLC), can even improve with age
- 11. • The leukodystrophiesare autosomal recessive (AR) or X-linked disorders that usually result from loss-of-function mutations in enzymes involved in either production of myelin or normal myelin turnover and degradation These enzymatic defects are not necessarily specific only to the CNS, and other organ systems may be affected. Clinically, these diseases typically present in early childhood with progressive loss of motor control, cognitive function, seizures, and eventual death
- 12. Cognitivedefecits an earlypresentation- hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) . Prominent features behavioural changes, mood changes and loss of realistic assessments of daily life experiences Bulbar symptoms at onset –Alexander disease Extrapyramidal signs and symptoms - dystonia and/or dyskinesias , are less frequent but might be a predominant manifestation in certain disorders, including progressive leukoencephalopathy with ovarian failure, various HLDs and AxD. Seizures – MLD , krabbes ,Alexander disease
- 13. Peripheral neuropathy Axonal –APBD Demyelinating -Krabbe ,CTX,MLD
- 14. • Occulomotor abnormalities- APBD (slow saccades) Type II AxD ,POL III (vertical gaze abnormality, nystagmus, slow saccades), • Abnormal eye movements/ nystagmus – Pelizius Merzbacker and like diseases • Palatal Myoclonus – Type II alexander disease. • Hearing abnormalities – X- ALD • Autonomic dysfunction - APBD, AxD, ADLD, • Dorsal coloumn dysfunction - APBD, CTX, LBSL
- 16. X- linked Adrenoleukodystrophy •Phenotypes include - cerebral inflammatory demyelinating form (adult cerebral X ALD (ACALD) ‑ , 5 % of affected adults as primary manifestation .Usually presents with psychiatric features followed by dementia, ataxia, seizures and death • Adrenomyeloneuropathy – more frequent , a slowly progressive spastic paraparesis, neurogenic bladder and bowel dysfunction, sexual dysfunction & peripheral neuropathy.( dying back axonopathy eventually leading to spastic ataxic gait in 3rd – 4th decade ). • Adrenal insufficiency is frequently associated.
- 18. • About 20%of female X linked ALD carriers develop symptoms, usually in their fourth decade (AMN-like phenotype) • Only very rarely do they have adrenal insufficiency
- 19. • Mutation -ABCD1 gene • Accumulation of very long chain fatty acids (VLCFAs) in the nervous system as well as in the adrenal glands, testis and body fluids. • Allogeneic haematopoietic stem cell transplantation(aHSCT) – only life saving option in ACALD . • Trials going on on exvivo lentiviral genetherapy ( transduction of autologous CD34+ cells ) • Prevention of neurodegeneration – administering biotin and PPAR – r agonist are under trial .
- 20. • MRI :White matter abnormalities are usually first seen in occipital regions, with early involvement of the splenium of the corpus callosum and posterior limbs of the internal capsule. • The changes then progress to involve more anterior regions. • In cerebral ALD, contrast enhancement at the periphery of the signal abnormalities is said to be characteristic
- 21. The Loes ScoringSystem. • The Loes scoring system is universally applied to quantify the extent of cerebral involvement. • Regions of the brain (such as parietooccipital white matter, anterior temporal white matter, visual pathway, corpus callosum, auditory pathway, basal ganglia, projection fibers, and cerebellum) are subdivided and scored based on the extent of disease . • With a score of 0 if normal, 0.5 if unilateral involvement is present, and 1 if the lesion or atrophy is bilateral. • Global atrophy is also assessed. • A normal MRI scan has a score of 0, and the maximum severity score is 34.
- 22. • Very-long-chain fattyacids, especially C26:0 and the ratios of C26:C22 and C26:C24, are elevated in all clinical phenotypes of X-linked adrenoleukodystrophy, and these abnormalities may be detected at birth, facilitating a diagnosis prior to symptom onset. • Biochemical abnormalities in cortisol production occur in 85% of all males with X-linked adrenoleukodystrophy; screening for this should begin during infancy, with regular testing throughout the life of an affected male
- 23. Metachromatic Leukodystrophy • ARlysosomal storage disorder • An enzyme deficiency of arylsulfatase A, which is encoded on the ARSA gene on chromosome 22 q/or pathogenic mutations in PSAP (which encodes prosaposin) • Sulfatides accumulate in the central and peripheral nervous systems, kidneys, testes, and visceral organs (gall bladder). • MLD is an adulthood leukodystrophy that is frequently misdiagnosed as early- onset dementia and/or a schizophrenic disorder, as the neurological symptoms can occur late in the disease course.
- 24. A high indexof suspicion for metachromatic leukodystrophy must exist for patients presenting with a peripheral neuropathy or gall bladder abnormality in the absence of other neurologic features. The MRI may not reveal pathology early in the disease course; therefore, a normal MRI is not sufficient to exclude metachromatic leukodystrophy.
- 25. Neuroimaging • Demyelinating disorder(T1 hypointense) with confluent T2 hyperintensities surrounding the frontal and parietal periventricular white matter . • In patients with diffuse disease, a striped (tigroid) appearance may be seen, in which normal white matter alternates with hyperintense lesions (also seen in other leukodystrophies, such as Pelizaeus-Merzbacher disease). • Sparing of subcortical U fibers and involvement of copus callosum.
- 26. • A lowarylsulfatase A level (less than 10% of normal values) is detected in white blood cells or cultured fibroblasts, confirmed by the detection of elevated sulfatides in the urine and ARSA sequencing for mutations • Arylsulfatase A pseudodeficiency - 5% to 20% of normal values without clinical or radiographic disease. • Phase 1/II trial of intrathecal aryl sulfatase A . • Juvenile MLD – autologous HSCT . • Genetherapy under trial .
- 27. Globoid Cell Leukodystrophy(Krabbe Disease) • Globoid cell leukodystrophy, or Krabbe disease, is an autosomal recessive lysosomal storage disorder caused by mutations in GALC on chromosome 14q31. • GALC encodes the enzyme galactosylceramidase, which is essential in the degradation of lipids (galactosylceramide and psychosine) during myelin turnover.
- 28. Krabbe disease • Adultform (10% of cases) • Presents with pyramidal tract dysfunction and spastic paraparesis. • Can also develop cognitive decline, seizures & cortical blindness. • 20% of patients abnormal NCS (slowing of conduction velocity)
- 30. • Krabbe diseaseis a demyelinating disorder (T1 hypointense) with confluent T2 hyperintensities with a periventricular or parietooccipital predominance. Posterior predominant white matter changes, with sparing of the U fibres and involvement of the splenium of the corpus callosum, are typically seen. T2 hyperintense changes are seen along the corticospinal tracts and the posterior limb of the internal capsule and pyramidal tracts of the brainstem. Axial T2-weighted MRI demonstrates confluent diffuse T2 high signal involving the central white matter and corpus callosum. The white matter has a striated and speckled appearance
- 31. Krabbe disease ina 48-year-oldman. (a) Axial FLAIR image shows bilateralparieto-occipital white matter involvement,extending to the splenium of the corpus callosum.(b) Coronal T2-weighted MR image also shows a posterior white matter involvement pattern extending to the corticospinal tracts bilaterally(arrows).
- 32. Cerebrotendinous Xanthomatosis • Autosomalrecessive disorder caused by mutations in the CYP27A1 gene, which encodes sterol 27-hydroxylase. • The deficiency of this enzyme results in the accumulation of cholesterol and cholestanol leading to premature arteriosclerosis,neurotoxicity and the formation of xanthomas in tendons, CNS, skin, and other organs.
- 33. • Adolescence withcataracts • In adulthood - spastic paraparesis, pyramidal tract signs, cerebellar ataxia, bulbar symptoms and peripheral neuropathy • Childhood history of diarrhoea or failure to thrive.
- 34. • If leftuntreated, patients can develop progressive dementia and psychiatric symptoms. • other organ involvement - tendon xanthomata (Achilles tendon), osteoporosis, respiratory, endocrine and liver involvement. • Elevated serum cholestanol levels and the presence of urinary bile alcohols are diagnostic features of CTX, • Long-term replacement of bile acid, especially with chenodeoxycholic acid (CDCA;750 mg daily) is the current best option.
- 35. • MRI :Non- specific supratentorial atrophy and deep periventricular white matter changes • Sparing of U fibres and corpus callosum are spared. • classic picture - high signal intensity within the cerebellar white matter and low signal intensity in the dentate nucleus on T2
- 37. Adult onset autosomaldominant leukodystrophy (ADLD) • Typically, patients present in 4th or 5th decade with autonomic abnormalities, followed by pyramidal symptoms, ataxia and cognitive deterioration MRI : • Diffuse white matter T2 hyperintensities involving the frontal lobe, parietal lobe and middle cerebellar peduncle. • Atrophy of the brainstem and corpus callosum
- 38. • ADLD iscaused by duplications of the LMNB1 gene on chromosome 5q23, which result in overexpression of lamin B1 protein. • Overexpression of this protein leads to disruption of myelin homeostasis and slowly progressive, non-inflammatory demyelination, predominantly in deep white matter structures and cerebral peduncle, mistaken for chronic progreesive MS.
- 39. Hereditary diffuse leukoencephalopathywith neuroaxonal spheroids (HDLS) • Adulthood -HDLS primarily manifests in the fourth or fifth decade of life with behavioural changes, depression,gait ataxia and early-onset dementia. • Frontal gait ataxia, rigidity, bradykinesia and resting tremor are frequently observed. • Inheritance is autosomal dominant, although sporadic cases are common.
- 40. • The genedefect affects the tyrosine kinase domain of macrophage colony- stimulating factor 1 receptor, encoded by CSF1R. MRI : Non-enhancing, symmetrical white matter T2 hyperintensity with a frontal predominance Also involving the precentral and postcentral gyrus, extending from the periventricular and deep regions to subcortical tissues.
- 41. • Associated atrophyin the regions of hyperintensity • Abnormal signal in the corpus callosum with or without atrophy • Signal abnormalities extend downwards through the posterior limb of the internal capsule into pyramidal tracts of the brainstem
- 42. Vanishing white matterdisease (VWM) • Spasticity, cerebellar signs, seizures and dementia. • 1/3rd with psychiatric symptoms. • Female patients - primary or secondary ovarian failure.
- 43. MRI : • DiffuseT2 hyperintensity and hypointensity with associated cystic change (FLAIR) and atrophy • Corpus callosal atrophy and T2 and FLAIR hyperintensities. • Cerebellar white matter changes • Atrophy of the cerebellar hemispheres. • End stage - cerebral hemispheric white matter may have vanished leaving a ventricular wall and cortex
- 45. Adult polyglucosan bodydisease (APBD) • APBD typically presents in the fifth to the sixth decade of life with a combination of upper and lower motor neuron impairment resembling amyotrophic lateral sclerosis,along with cerebellar ataxia or Parkinson disease-like symptoms with extrapyramidal movement disorders. • In some patients, polyneuropathic symptoms with hyporeflexia, distal symmetric sensory loss, muscle atrophy and fasciculations can be prominent, with slowed nerve conduction velocity and denervation potentials on electrophysiological testing. • Cognitive deficits, reflecting white matter involvement, tend to be very mild.
- 46. MRI • Diffuse periventricularwhite matter changes predominantly the occipital and temporal lobes and the mesencephalon and cerebellum. • Most prominent in the periventricular region, posterior limb of the internal capsule and external capsule . • Later stages - thinning of the corpus callosum diffuse cerebral, cerebellar and spinal cord atrophy
- 47. • The affectedgene in APBD, GBE1, encodes a glycogen- branching enzyme (GBE1), dysfunction of which leads to accumulation of polyglucosan bodies in the central and peripheral nerves. • Triheptanoin diet( 7 carbon triglyceride ) therapy under trial
- 48. Pelizaeus-Merzbacher disease (PMD) andPelizaeus-Merzbacher-like disease • Limited case reports in adults • PMD -common presentation of spastic paraplegia. • Adult type may present with a chronic neurological syndrome including tremor, ataxia and dementia
- 49. Differential diagnoses foradulthood leukodystrophies • Inherited vasculopathies with white matter involvement –CADASIL ,CARASIL • Inherited CNS diseases with grey and white matter involvement- fragile x ataxia syndrome ,DRPLA • Inborn errors of metabolism • Other disorders with white matter involvement like Wilson,s Disease • Acquired inflammatory, toxic, and traumatic white-matter predominant central nervous system disorders
- 50. Adult Leukodystrophies: AStep by- Step Diagnostic Approach Based on imaging
- 51. • MRI isa key tool in differentiating leukodystrophies. • On T2-weighted images, symmetric hyperintensities occur in various regions depending upon the underlying disorder. • Typically the affected white matter is significantly hypointense on T1-weighted images; however, a distinct subgroup, the hypomyelinating leukodystrophies, are isointense or hyperintense (or sometimes mildly hypointense) on T1- weighted images
- 52. Step 1 IdentifySymmetric White Matter Involvement • Symmetric white matter involvement at MRI is a typical finding in patients with leukodystrophies..exceptions – APBD ,VWMD ,HDLS (a) Axial T2-weighted MR image in a 23-year-old woman with leukoencephalopathy with brainstem and spinal cord involvement shows symmetric white matter involvement. (b) Axial FLAIR MR image shows an asymmetric pattern in a 46- year-old woman with cerebral autosomal dominant arteriopathy with subcortical infarcts andleukoencephalopathy (CADASIL).
- 53. Step 2: Lookfor a White Matter Involvement Pattern
- 55. Step 3: RecognizeDistinctive Features
- 56. Cerebral inflammatory demyelinatingvariants of X linked adrenoleukodystrophy ‑ (X ALD) with frontal (part f) or parieto-occipital (part g) predominance. Note the ‑ contrast enhancement marginal to the demyelinated areas (arrows)
- 57. Hypomyelination in anadult with a Pol-III-related leukodystrophy. Arrow indicates moderately increased T2 weighted signal ‑ in affected white matter. Note relative atrophy, which is common in adults with hypomyelination. Severe cerebellar atrophy in a 24 year-old ‑ female with Pol-III- related hypomyelinating leukodystrophy. Diffuse cerebral white matter changes in a 61 year-old male ‑ with vanishing white matter disease. Note rarefaction of affected white matter (arrow) on fluid-attenuated inversion recovery images.
- 59. Assessment and Diagnosis •Initial assessment should focus on the exclusion of common acquired causes and severe small vessel disease(round 1). • If these initial tests are negative and the patient is suspected to have a genetic disorder, then the first line of testing should include white cell enzyme activities, a VLCFA profile(in men), plasma cholestanol and bile alcohols and plasma amino acids, to exclude the classical leukodystrophies which can present in adulthood
- 65. Evolving Therapeutic Approach Multimodaltherapy approaches have the highest potential not only of halting but also repairing the complex and multifactorial pathology of leukodystrophies. The CRISPR (clustered regularly interspaced palindromic repeats)-Cas (CRISPR-associated protein) approach is a promising method for precise gene editing,
- 66. • Orphan diseasessuch as leukodystrophies frequently pose severe problems, particularly with respect to early diagnosis and research awareness. • Targeted genetic testing using next-generation sequencing techniques, will enable the identification of previously undetected or unknown leukodystrophies in adult patients, • Multimodal therapy approaches are applied with increasing success and are superior to unimodal approaches in halting the disease process and repairing the multifactorial complex pathology of leukodystrophies.
- 67.