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Metabolic Disorders for the RITE Andrew Mundwiler With recognition of Jeanie Cote, Ben Bly, Rani Singh Objectives • Review presentations of adult and pediatric metabolic disorders commonly encountered on the RITE • Familiarize with common imaging characteristics of metabolic disorders • Differentiate between various leukodystrophies clinically and radiographically Outline • • • • • • • Peroxisomal Disorders Mitochondrial Disorders Amino Acid Disorders Urea Cycle Disorders Lysosomal Storage Disorders Glucose and Glycogen Storage Disorders One in the category of “other” • The Leukodystrophies Case • • • • • • 5 year old boy Regression Nausea, vomiting, Hypotension Deafness Elevated C:26 Peroxisomal Disorders • Peroxisomes catabolize long fatty acids • Leads to dysfunction of myelin -> neuronal dysfunction, migration defects • Dysmorphic features in some • KEY: elevated VLCFA – Adrenoleukodystrophy – Zellweger Syndrome – Refsum Disease Adrenoleukodystrophy • Mentioned almost every year in answer explanations, questioned directly in 2012 and 2014 • ALD protein (ALDP) encoded by ABCD1 gene – Transport of VLCFA to peroxisome – Accumulation of VLCFA in tissue, esp. adrenal cortex and oligodendrocytes Adrenoleukodystrophy • Features – X-linked – Adrenal insufficiency (FTT, hypoglycemia, lethargy, n/v/d, hypotension – Neurologic • Infantile: Regression, attentional symptoms, vision loss, impaired visuo-spatial functioning, deafness, spasticity, ataxia • Adrenomyeloneuropathy: Neuropathy, paraparesis, spasticity, cognitive impairment, arising in 20s-30s – Elevated VLCFA (C26:0, C26:0/C24:0, C26:0/C22:0) Adrenoleukodystrophy • Imaging – Posterior predominant – Spares U-fibers – May contrast enhance 2014 exam Zellweger Syndrome • Asked once in 2012 • Onset in infancy • Dysmorphism: prominent forehead, hypoplastic supraorbital ridge, midface hypoplasia • Weakness, hypotonia, and seizures are common • Renal cysts and liver fibrosis • Elevated saturated and unsaturated VLCFA Zellweger Syndrome Case • • • • Adolescent boy Poor night vision Sensory loss in feet Exam also reveals mild ataxia and palpable peripheral nerves Refsum Disease • Asked once in 2012, mentioned in answer explanation in 2011 • Clinical Manifestations – Neuropathy – Enlarged, palpable nerves – Ataxia – Retinitis pigmentosa – Hearing loss – Cardiac disease Refsum Disease • Caused by impaired alpha-oxidation of phytanic acid (a branched FA) • Treatment is limiting phytanic acid in diet, or in severe cases PLEX Amino Acid Disorders • Glutaric Aciduria • Organic Acidemias – Methylmalonic acidemia – Propionic acidemia • Aminoacidopathies – – – – PKU MSUD Homocysteinuria Nonketotic hyperglyceinemia • Urea Cycle Disorders – Ornithine transcarbamylase (OTC) deficiency – Et al Case • 9 month old baby born with macrocephaly • Developed hyperkinetic movements in the setting of URI • MRI shows temporal lobe atrophy and subdural fluid collections Glutaric Aciduria • 4-5 questions in last 6 years, included in an answer another time • Inability to break down lysine, hydroxylysine, and tryptophan • Commonly born macrocephalic • +/- developmental delay • Hypotonia • Often acute onset with hyperkinetic movement disorder in the setting of intercurrent infection • Can have insidious course • Treatment with carnitine may slow progression Glutaric Aciduria • Temporal atrophy with enlarged Sylvian fissures • Increased signal and restricted diffusion in the basal ganglia, dentate nucleus, substantia nigra, and pontine medial lemniscus • Subdural hematomas or fluid coillections (not shaken baby syndrome) Organic Acidemias • Methylmalonic acidemia – – – – Deficiency of methylmalonic CoA mutase AR MRI: globus pallidus infarction PAA/UOA: elevated MMA w/o hyperhomocysteinemia or homocysteinuria – Treat with protein restriction and B12 • Propionic acidemia – – – – – Deficiency of proprionyl CoA carboxylase AR MRI: basal ganglia infarction PAA/UOA: elevated plasma glycine and propionate Skin fibroblasts show decreased enzyme activity Aminoacidopathies • Phenylketonuria – Deficient phenylalanine hydroxylase – AR – Decreased pigment (blonde, blue eyes) – Progressive MR – Seizures, spasms – Increased serum phenylalanine and urine phenyl ketones – Treatment: restrict phenylalanine Aminoacidopathies • Maple Syrup Urine Disease – Deficiency of branched-chain alpha-keto acid dehydrogenase complex – AR – FTT, vomiting, seizures, death in first weeks if untreated – Smell like maple syrup – Elevated serum leucine, isoleucine, valine – Elevated urine branched chain amino acids Aminoacidopathies • Homocystinuria – – – – Included in 2012 as an answer choice Cystathionine beta synthase deficiency AR Typically present as adults • • • • • Marfanoid habitus MR Seizures Downward lens subluxation Atheroma formation/thrombotic tendency – Elevated serum homocysteine and methionine – Treatment: Protein restriction, B6, Vitamin B12, folate, ASA Aminoacidopathies • Nonketotic Hyperglycinemia – Defects in glycine cleavage system (GCS) – AR – Neonatal encephalopathy. Myoclonus, seizures, hypotonia. – Sympoms begin within 6-8 hours of life. Progresses to coma and often death. – CSF glycine is elevated (CSF/Plasma > 0.06) Urea Cycle Disorders • Carbamoyl phosphate synthetase I (CPSI) deficiency • Ornithine transcarbamylase (OTC) deficiency (X-Linked) • Argininosuccinate synthetase (ASS) deficiency aka classic citrullinemia • Argininosuccinate lyase (ASL) deficiency • N-acetyl glutamate synthetase (NAGS) deficiency • Arginase deficiency 23 Urea Cycle Disorders • Lethargy, poor feeding, vomiting, hypotonia soon after starting feeds • Hyperammonemia, cerebral swelling • Life threatening metabolic decompensations w/ seizure, coma, strokes • Diagnose by PAA, fibroblasts on skin biopsy, or liver biopsy • Do not treat with valproate, associated with hyperammonemia 24 Lysosomal Storage Disorders • Examples – Niemann Pick – Krabbe – Fabry – Metachromatic Leukodystrophy – Gaucher – GM1 gangliosidosis – GM2 gangliosidosis (Tay-Sachs) – Neuronal Ceroid lipofuscinoses 25 Niemann-Pick Disease • • • • • Tested 2011 and 2014; incorrect answer once Type A/B/C AR “Cherry red spot” Type A: classic infantile – Progressive neurologic decline, death by age 2 • Type B: visceral (HSM, thrombocytopenia) – Later onset (preteen) – Neurologic symptoms are not prominent 26 Niemann-Pick Disease • Type C – Mutation of NPC1 or -2 gene, involved in trafficking lipids in cells – AR – Onset in adolescence – Progressive neurologic decline • Vertical supranuclear gaze palsy • Ataxia • Dystonia • Seizures • Gelastic cataplexy • Dementia – Hepatosplenomegaly 27 Tay Sachs Disease • Deficiency of: – Hexosaminadase A • Asked once in 2009 • AR 28 Tay Sachs Disease • Infantile: onset 3-6 mo – Excessive startle reflex, hypotonia, regression, irritability. – Cherry red spot – Progresses to myoclonic seizures, blindness – Increasing head circumference during 2nd year of life – Death by 4-5yrs • Juvenile: onset 2-10 yrs – Ataxia, regression, dementia, +/- cherry red spot – Late optic atrophy and retinitis pigmentosa – Death by 10-15 years • Incorrect answer in 2014, EEG shows slow background with or without multifocal epileptiform transients (as opposed to periodic discharges) 29 Case • • • • • 24 year old man Mildly elevated creatinine Complains of painful distal sensory loss Frequent fainting when standing Erectile dysfunction 30 Case • Angiokeratoma – Painless papules predominating on the lower body 31 Fabry Disease • Asked essentially yearly • Deficiency of alpha-galactosidase A • X-linked • Present in 2nd or 3rd decade • Painful peripheral neuropathy with autonomic dysfunction • Rash on lower body (angiokeratoma) • Glycolipid accumulation in endothelium of cerebral blood vessels and glomerular arterioles – Premature CV events as adults – Renal impairment • Enzyme replacement therapy slows progression if started early (asked in 2010) 32 Gaucher • • • • Incorrect answer in 2010 and 2014 Deficiency of the glucocerebrosidase AR HSM, thrombocytopenia, anemia, bleeding, osteopenia 33 Gaucher • Type 1: 90%. Non-neurologic • Type 2: – onset < 1 yo, death by 2 yo. – Seizures, profound retardation, apnea, hypertonia, icthyosis – Increased tone (spasticity as opposed to hypotonia) • Type 3: – Childhood onset, death between 20 yo vs “shortened” – Supranuclear gaze palsy, myoclonus, dementia, ataxia 34 GM1 gangliosidoses • Deficiency of beta-galactosidase • AR • Type 1 (infantile) – Neurodegeneration, Cherry Red, organomegaly, coarse facies, seizures, cardiomegaly, death by 2 • Type 2 (Juvenile) – Neurodegeneration, cherry red, seizures, cardiomegaly • Type 3 (adult) – Progressive dementia, dysarthria, parkinsonisms. 35 Krabbe Disease • Asked every year (except last), included as answer on several questions in past 3 years • Deficiency of galactocerebroside-betagalactosidase • AR • Diffuse abnormal myelination centrally • Demyelinating sensory motor neuropathy 36 Krabbe Disease • Microcephalic/normocephalic (NOT macrocephalic) • Infantile form presents with dramatic encephalopathy at 3-4 months • MRI with diffuse white matter signal SPARING the Ufibers, no enhancement • Nerve Bx: sphingolipid deposits 37 Metachromatic Leukodystrophy • • • • Showed up last 4 years Deficiency in arylsulfatase A AR Similar to Krabbe: central white matter and demyelinating peripheral neuropathy (sphingolipid deposits on nerve biopsy) • No megalencephaly • MRI: anterior predominant, confluent, periventricular, spares U-fibers 38 Metachromatic Leukodystrophy 2014 39 Neuronal Ceroid Lipofuscinosis • Rarely included as an incorrect answer • Multiple types based on age of presentation, prognosis, etc. • Progressive neurodegeneration, seizures • Visual loss is a common feature • Affects gray matter (thalami, basal ganglia) more than white matter 40 Mucopolysaccharidoses • I: Hurler – AR – Alpha-L-iduronidase – Normal at birth – 6mo-2yrs, HSM, facies, stiff, delay, corneal clouding – Death by 5-10 yrs • II: Hunter – X-linked (x marks the hunters spot) – Iduronate-2-sulfatase – Normal at birth – 2-4 yrs onset • No corneal opacities • + ivory colored skin lesions 41 Glucose and Glycogen Storage Disorders • Galactosemia • Larora Body • Glycogen Storage Disorders – Pompe – McArdles 42 Galactosemia • Deficiency in galactose-1-phosphate uridyltransferase • AR • Neonates: poor feeding, vomiting, lethargy – Associated jaundice, hepatomegaly – Cataracts by week 2 – Long term features : Speech Dyspraxia, cognitive delay, Extrapyramidal symptoms • Tx: restrict galactose 43 Lafora (Body) Disease • • • • • • Asked in 2010, 2013 (pathology) AR Mid-teen onset Myoclonic epilepsy Rapid neurocognitive deterioration Supportive care 44 Lafora (Body) Disease • Rounded, targetoid inclusions. • Often found in cerebral cortex • Demonstrated in virtually every tissue (i.e. skin biopsy) 45 Glycogen Storage Disorders • Pompe (GSD II) – Asked every year – Acid maltase (alpha 1-4 glucosidase) deficiency – Presents at about 2 months with • • • • • • FTT Cardiomegaly Hepatomegaly Progressive weakness Macroglossia with tongue fasciculations Hypotonia 46 Glycogen Storage Disorders • Pompe (GSD II) – Associated with aneurysmal dilation of cerebral arteries, esp. fusiform aneurysm of the basilar artery – Muscle biopsy with PAS+ glycogen in membranebound vacuoles 47 Glycogen Storage Disorders • McArdle Disease (GSD V) – Myophosphorylase deficiency – Adolescence • • • • Cramps, fatigue after initiating exercise. Second Wind phenomenon Elevated CK, post-exertional myoglobinuria Failure of normal rise in lactate – Muscle biopsy with glycogen storage (PAS positive) in muscle and absence of myophosphorylase – Only affects skeletal muscle, not liver 48 Other • Lesch-Nyhan – Deficiency of hypoxanthine-guanine phosphoribosyltransferase – Dystonia/chorea by 12 months – Self-injurious behavior by 2-4 years 49 Leukodystrophies 50 Leukodystrophies • Disorders of myelin development due to an inherited or spontaneous genetic mutation. These disorders cut across the categories of inborn metabolic disorders. Examples include: – X-linked adrenoleukodystrophy (peroxisomal) – adrenomyeloneuropathy (peroxisomal) – Metachromatic leukodystrophy (lysosomal) – Hereditary CNS demyelinating disease – Krabbe disease (lysosomal) – Pelizaeus-Merzbacher disease – Canavan disease – Leukoencephalopathy with vanishing white matter (childhood ataxia with central nervous system hypomyelination (CACH) or vanishing white matter disease.) – Alexander disease – Cerebrotendineous xanthomatosis 51 Canavan Disease • Asked frequently in recent years; last year, only incorrect response • Aspartoacylase deficiency • AR • Spongiform leukoencephalopathy • No involvement of PNS • Presents at 3 mo: lethargy, FTT, floppy – Macrocephaly (brain enlarged, not atrophied, initially) – Spasticity, extensor spasms – Development essentially stops by 6 mo – Blindness, seizures 52 Canavan Disease • MRI: Diffuse, symmetric WM involvement – Extensive involvement of U-fibers – Microcysts in the setting of macrocephaly • NAA elevated on MRS and in urine 53 Alexander Disease • • • • Asked frequently in recent years Sporadic Mutation in glial fibrillary acidic protein (GFAP) gene Pathologic hallmark is profuse Rosenthal fibers (“densely compacted glial intermediate filaments made of GFAP”) Also seen in pilocytic astrocytoma 54 Alexander Disease • Associated with megalencephaly (along with Canavan) • MRI: – Involves U-fibers (as does Canavan) – Frontal predominence – Contrast enhances (as does adrenoleukodystrophy) 55 Pelizaeus-Merzbacher Disease • • • • • Showed up on last 2 years Deficiency of proteolipid protein AR or X-linked Course nystagmus Diffuse WM involvement (hasn’t been an image question) 56 Cerebrotendinous Xanthomatosis • Included as answer in 2011 (image of neurosarcoid in GM, needed to know that CTX was a white matter dz) and 2014 (affects primarily the cerebellum) • AR • Deposition of cholesterol in brain and other tissues, with normal serum cholesterol levels • Ataxia after puberty, juvenile cataracts, diarrhea during infancy • Dementia, seizures, hallucinations, depression in adulthood • Tendinous xanthomas 57 Leukodystrophy Review • Blah blah, baby, head circumference >97% • MRS shows elevated NAA spike • What is it? 58 Leukodystrophy Review • Blah blah, baby, head circumference >97% • MRS shows elevated NAA spike • What is it? • Canavan Disease 59 Leukodystrophy Review • U-fibers involved? • Choices: A: Alexander disease B: Wilson’s disease C: Canavan disease D: Krabbe disease 60 Leukodystrophy Review • U-fibers involved? – No • Choices: A: Alexander disease B: Wilson’s disease C: Canavan disease D: Krabbe disease 61 Leukodystrophy Review • U-fibers involved? – No • Choices: A: Alexander disease B: Wilson’s disease C: Canavan disease D: Krabbe disease 62