Leukodystrophy - updated for questions PDF

White Matter Disorders Swaiman Ch 99 Van der Knapp articles Leukodystrophies Heritable myelin disorders affecting CNS (and sometimes PNS) white matter Differentiate from other acquired processes Endocrine dysfunction – congenital & acquired thyroid and adrenal dysfuncti...

White Matter Disorders Swaiman Ch 99 Van der Knapp articles Leukodystrophies Heritable myelin disorders affecting CNS (and sometimes PNS) white matter Differentiate from other acquired processes Endocrine dysfunction – congenital & acquired thyroid and adrenal dysfunction Nutritional factors – Vitamin B12 deficiency Acquired – periventricular leukomalacia, toxic or infectious process Clinical: progressive spasticity, bulbar symptoms, preserved cognition Rads Two main types Hypomyelinating – Hyper T2, iso/hyper T1 Demyelinating – Hyper T2, Hpo T1 Hypomyelinating White Matter Disorders Pelizaeus-Merzbacher Disease 4H Syndrome Trichothiodystrophy Cockayne Syndrome Hypomyelinating WM Disorders 20% of leukodystrophies Permanent deficit of myelin Most AR, but do have XL and de novo Clinical: ataxia, spasticity and nystagmus Dx: MRIs 6 months apart >12mo of age show little of no myelin development Hyperintense WM T2, iso/hyper EM T1 Pelizaeus-Merzbacher Disease PLP1, Xq22.2 – usually duplication Clinical features: Pendular nystagmus in infancy  delay, axial hypotonia, dystonia/chorea Connatal form: congenital stridor, feeding difficulties, profound hypotonia Allelic with x-linked spastic paraplegia type 2 (SPG2) Also caused by PLP1 mutations Pure form: progressive spasticity Complicated form: spasticity + nystagmus, ataxia, dysarthria, mild cognitive impairment Pelizaeus-Merzbacher Disease MRI of 23mo Supratentorial axial T2-weighted images show homogeneous hyperintense white matter signal, indicating profound hypomyelination Lack of myelin in cerebellum Thin corpus callosum Pelizaeus-Merzbacher-like disease GJC2 gene mutation (connexin 47), AR Nystagmus, hypotonia  ataxia, spasticity Milder than PMD MRI: brainstem signal abnormalities and atrophy 4H Syndrome Triad of hypomyelination, hypodontia and hypogonadotropic hypogonadism POLR3A or POLR3B, AR Clinical features: Normal development until 18mo  frequent falls, ataxia, dysmetria, nystagmus Progressive motor decline, cognition less impaired Hypodontia/disordered eruption of teeth, natal teeth Low FSH/LH MRI: cerebellar atrophy Tx: Growth hormone if deficient; hormone supplementation to induce puberty and prevent osteoporosis Oculodentodigital dysplasia GJA1 gene (connexin 43), AR Diagnosed based on dysmorphic features Microphthalmia, dental anomalies, syndactyly Mild neuro symptoms: ataxia, spasticity Salla Disease Sialic acid storage disorder Sialic acid accumulates in lysosomes SLC 17A5, AR Clinical features: Normal early development  6 months: hypotonia, nystagmus  spasticity, dystonia Seizures Coarse facial features MRI: thin CC, cerebellar atrophy MRS high NAA peak (sialic acid peak coresonates) Cockayne Syndrome Gene mutation in CSA, CSB, XPB, XPD Type I: presents in 1st year of life with FTT, microcephaly, bird-like face Non-neuro: contractures, large hands/feet, dental caries, cutaneous photosensitivity, cataracts Neuro: cognitive disability, delayed psychomotor development, ataxia, SNHL, peripheral neuropathy Type II: more severe – IUGR, contractures, hypotonia, severe loss of sq fat MRI: basal ganglia calcifications Trichothiodystrophy Gene mutations in CSA, CSB, XPB, XPD (same as Cockayne) Clinical features: Thin, brittle kinky hair  hair loss with fever Dystrophic nails, cutaneous photosensitivity, ichthyosis Neuro: delay, cog impairment, spasticity, cataracts SOX10-associated disorders SOX10 mutation, 22q13 gene Clinical features: White hair lock, hypomelanotic spots, SNHL Hirschsprung disease Congenital arthrogryposis multiplex White Matter Disorders with Demyelination Alexander X-linked adrenoleukodystrophy Metachromatic leukodystrophy  Alexander Disease GFAP mutation, Ch17, usually AD; Rosenthal fibres on bx Type I: present 4yr of age Progressive ataxia, spasticity, fine motor impairment (milder) Prominent bulbar symptoms: dysphagia, dysphonia, palatal myoclonus (ass with brainstem lesions, Guillain- Mollarett triangle) Dysautonomia, sleep apnea MRI atypical – posterior/brainstem predominant, supratentorial WM spared  X-linked Adrenoleukodystrophy ABCD1 gene, peroxisomal membrane transporter, XL Childhood: school-aged (4-8yr) boys behaviour/cognitive change (new onset ADHD), motor difficulties, altered perception of speech, vision & hearing problems, spasticity, adrenal insufficiency Adrenomyeloneuropathy (AMN): adult onset (males 20-40s) progressive gait abnormalities, abnormal sphincter control, sexual dysfunction Isolated adrenal insufficiency: can presents in Addisonian crisis Ix: elevated VLCFA, genetic MRI: occipital predominance, hyperT2, hypo T1, rim of enhancement Tx: hematopoietic stem cell transplant Hydrocortisone supp for Addison syndrome Lorenzo’s oil: decreases hexacosanoic acid (not recommended anymore) Metachromatic Leukodystrophy (MLD) ARSA gene, encoding Arlsulfatase A, ch22q, AR Clinical: Late infantile: present by 2 yr with gait disturbance, ataxia, dysarthria, motor regression, peripheral neuropathy (misdiagnosed as CIDP), ophthalmoparesis Tonic spasms, seizures Spasticity, hearing loss, cherry-red spot, Juvenile: 2-16yr Cognitive/behaviour decline; spasticity, ataxia, dysarthria Adult Motor impairment + peripheral neuropathy Neuropsych symptoms, cognitive decline  MLD MRI: Confluent periventricular changes, sparing arcuate U-fibres Radial stripes.: tigroid appearance Butterfly pattern CC involved MRS: high choline Ix: low arylsulfatase A in blood, high urinary sulfatides, genetics Tx: Cholecystectomy for gallbladder dysfunction, polyps and to prevent cancer Hematopoietic stem cell transplant in early cases  Krabbe Disease (Globoid Cell Leukodytrophy) GALC gene, AR, ch14q31, deficiency of galactosylceramidase Infantile: onset 6mo of life Stage I: irritability, hypertonia, peripheral nerve involvement Stage II: opisthotonic posture, optic atrophy, seizures, spasticity Stage III: blindness, decerebrate posturing Late onset (>6mo) Vision loss, spasticity, developmental regression Juvenile (>4yr) + adult onset Gait dysfunction, spastic paraparesis Cognitive/behaviour decline, seizures Demyelinating peripheral neuropathy Slower progression than infantile-onset Krabbe disease Ix: CSF: increased protein NCS: demyelinating peripheral neuropathy (prolonged motor conduction velocities) Path: globoid cells in affected WM Low GALC enzyme activity in skin fibroblasts CT: hyperdense thalami, caudate, cerebellum Basal ganglia/thalamic calcifications MRI: changes in brainstem & dentate nucleus PLIC, WM, thalami Thickened optic nerves & chiasm, brain atrophy Periventricular white matter, U-fibre sparing, involving CC Radiating (tigroid) stripes Tx: HSCT in very early stages Sjogren-Larsson syndrome FALDH (fatty aldehyde dehydrogenase) gene, AR Ichthyosis, progressive spasticity, intellectual disability MRI: periventricular WM disease MRS: lipid peak **neuroichthyosis syndromes (associated with icthyosis or ichthyosiform dermatoses to central or peripheral nerves) Combines intellectual disability and spastic diplegia with congenital ichthyosis Majority bron prem, spasticity between 4-30 mo, most in LE All have cog impairment caries from slight to severe, almost all have mild to moderate dysarthria and 1/3 have epilepsy Atypical retinitis pigemtnosa with macular glistening dots is almost constant feature Peripheral involvement Dietary treatment is NOT successful Diagnosis depends on measurement of fatty aldehyde or of oxidorecutase comoplex in fibroblasts in sin biopsies Vacuolization Leukodystrophies Canavan Vanishing White Matter MLC  Canavan Disease Deficiency of aspartoacylase, ASPA gene, AR, Ashkenazi Jews Clinical: present at 3-6mo with hypotonia, regression, irritability, macrocephaly  spasticity, seizures, optic atrophy, chorea Congenital variant: rapid encephalopathy Ix: MRS - NAA peak; urine high NAA Path: spongy degeneration MRI: confluent subcortical WM involvement + globus pallidi and thalami Caudate and putamen spared  Vanishing White Matter Disorders Aka Cree leukodystrophy aka ovarioleukodystrophy aka childhood ataxia with CNS hypomyelination Mutation in EIF2B1-5, AR Clinical: Infantile: deterioration after physiologic stress (fever, falls, fright), acute events include motor dysfunction, hypotonia, ataxia  coma Connatal form: encephalopathy + ovarian dysgenesis, cataracts, hepatosplenomegaly Adult: progressive spastic paraparesis MRI: diffuse supratentorial WM abnormality with cystic changes Diffuse WM changes, looks like fluid/CSF Basal ganglia spared Tx: Avoid head trauma; prompt treatment of fever and infections Treatment of ovarian failure  Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC) Mutation in gene encoding MLC1 protein, HEPACAM, AR Clinical: macrocephaly, temporal lobe subcortical cysts, spastic ataxia, epilepsy MRI: swollen subcortical WM Diffuse signal abnormality with preserved central structures (CC, IC, brainstem) Subcortical cysts (temporal/frontal) Tx: Avoid head trauma and prompt treatment of status epilepticus Calcifying Leukoencephalopathies Aicardi-Goutiere Aicardi-Goutieres Syndrome Multiple genes – TREX1, ADAR1, SAMHD1, IFIH1, autosomal recessive Clinical: subacute encephalopathy, dystonia, spasticity, microcephaly Mimics TORCH infections in neonates (hemolytic anemia, thrombocytopenia, transaminitis, seizures) Ix: elevated CSF alpha interferon MRI: intracranial (basal ganglia/WM) calcifications Allelic disorder: retinal vasculopathy with cerebral leukodystrophy (RVCL) Retinal vasculopathy, migraine, Raynaud’s, stroke Also: TREX1 associated lupus  Aicardi-Goutieres Syndrome Minimal criteria for diagnosis: Intracranial calcifications with abnormal WM and no infectious hx Characteristic clinical findings (chilblain skin lesions) CSF findings of pterins, alpha interferon Very early onset in first weeks or motnhso life Gneral condition is porr Marked hypotonia, opisthotonic episoes, failure to deveop, febrile episodes, death in a state oc decerebration within a few years 2 major diagnostic feaures - presence of calcifications of the basal nucleis also of the perventricular WM and dendate nucleus associated hypodensities of the WM and brain atropjy Persistent mild CSF lympocytosis that is not constant and tends to decrease with time Otuside the NS – low platelets, HSM, elevated trasnaminases along with intermittent fever Cutaneous lesions (chilblain like) present in half of cases Elevated interferon alpha are present in most cases in first years of dease and lesser estendt blood Similar cases reported as “cree encephalitis” from highly consangious first nations communties in Quebec  Wide phenotypic spectrum Affected individuals later onset and may not have sesvere or pressive neuro dysfunction, calcifications of BG, or CSF lymphocytosis 7 different forms ASG1-7 caused by mutations in various genes (recessive and dominant ith variable penetrance, inheritance patterns) Others Cockayne Syndrome Bandlike intracranial calcifications with simplified gyration and polymicrogyria Leukoencephalopathy with calcifications and cysts Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) CTC1 gene Microvascular disorders affecting brain, eyes (telangeictasias), liver, bones (spontaneous fractures) CMV Cadasil (cerebral AD arteriopathy with subcortical infarcts and leukoencephy): NOTCH3 mutation Migraines, progressive CVS, cognitive decline CARASIL: HTRA1 gene Mitochondrial Leukoencephalopathies MNGIE (mitochondrial neuro GI encephalopathy) Progressive GI dysmotility, ophthalmoplegia, hearing loss, demyelinating peripheral neuropathy Pyruvate carboxylase deficiency Infants with lactic acidosis, developmental delay, seizures Glutaric acidemia type II AKA multiple acylCoA dehydrogenase deficiency Episodic hypoglycemia, acidosis, coma, cardiomyopathy Sweaty feet odour General Treatment Spasticity – botulinum toxin, intrathecal baclofen, selective dorsal rhizotomy Maintenance of sufficient nutritional state (G-tube) Prevention (prophylactic antibiotics) and treatment of infections Treatment of bladder and bowel dysfunction Monitoring and treatment of ortho issues e.g., hip dislocation & scoliosis Calcium and Vitamin D supplementation Neuropathic pain – amitriptyline, gabapentin Irritability and disturbed sleep – melatonin Sialorrhea – glycopyrrolate, botulinum toxin Epilepsy – AEM Ensure adequate communication Adult Onset Leukoencephalopathies Childhood Leukodystrophies with Adult forms Metachromatic leukodystrophy Behaviour, tigroid pattern Adult-onset Alexander disease Adult onset X-linked adrenoleukodystrophy Brainstem, posterior MRI Adult onset Krabbe disease Spastic paraparesis and demyelinating peripheral neuropathy, posterior MRI Vanishing White Matter Disease CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy Clinical features: Migraine with aura Subcortical infarcts Cognitive impairment Encephalopathy Psychiatric features MRI features: WM T2 hyperintensities in temporal lobe & external capsule, CC signal change Lacunar infarct and microbleed Dx: NOTCH3 gene CARASIL: baldness and spondylosis Cerebrotendinous Xanthomatosis AR, CYP27A1 Clinical features: Behavioural Progressive cognitive decline Cerebellar signs Palatal myoclonus Skin changes: tendon xanthomas MRI features: Signal abnormality dentate, substantia nigra, globus pallidus Dx: high serum cholestanol Polyglucosan body disease GBE1 gene, AR Allelic to GSD IV Clinical features: Onset in 60s with ataxia and parkinsomism UMN and LMN features, distal sensory neuropathy Slowly progressive cognitive deficits MRI: confluent WM abnormalities, spares U-fibres and CC Early on, misdiagnosed as MS Autosomal dominant leukodystrophy with autonomic disease LMNB1 gene, AD Onset 60s Clinical features: Slowly progressive ataxia, cognitive impairment, autonomic dysfunction Urinary urgency, constipation, impotence, postural hypotension MRI: confluent Ddx Macrocephaly Canavan disease Alexander disease Megalencephalic leukoencephalopathy with subcortical cysts (MLC) Hemimegalencephaly syndromes Hypomelanosis of Ito NF1 Glutaric acidemia type I Ddx Frontal Predominance Alexander disease Metachromatic leukodystrophy X-ALD frontal variant