Metabolic Disorders PDF

Metabolic Disorders Ratika & AnneMarie’s Notes Classification Definition: results from absence or abnormality of enzyme or its cofactor leading to either accumulation or deficiency of specific metabolite Classified based on type of metabolism involved Classification Small Molecule di...

Metabolic Disorders Ratika & AnneMarie’s Notes Classification Definition: results from absence or abnormality of enzyme or its cofactor leading to either accumulation or deficiency of specific metabolite Classified based on type of metabolism involved Classification Small Molecule disorders  typically associated with acute/progressive intoxication or encephalopathy Amino Acid Disorders PKU, Tyrosinemia, MSUD Organic Acid Disorders MSUD, MMS, Propionic Acidemia, Isovaleric Acidemia, etc. Urea Cycle Disorders OTC deficiency, CPS, N-acetylglutamate synthetase deficiency Carbohydrate Intolerance Disorders Galactosemia, Hereditaroy fructose intolerance, galactokinase deficiency Classification Disorders of Energy Generation Glycogen Storage Disease/Glycogenesis Liver glycogen synthase deficiency (GSD 0), Glucose-6-phosphatase deficiency (GSD I; von Gierke disease), Lysosomal acid maltase deficiency (GSD II; Pompe disease), Glycogen debrancher deficiency (GSD III; Cori/Forbes disease), Glycogen branching enzyme deficiency (GSD IV; Andersen disease) Muscle phosphorylase deficiency (GSD V; McArdle disease), Liver phosphorylase deficiency (GSD VI; Hers disease), Muscle phosphofructokinase deficiency (GSD VII; Tarui disease) Gluconeogenesis Pyruvate Carboxylase Defic, pyruvate dehydrogenase deficiency, etc. Mitochondrial disorders Leighs, Kearns-Sayre syndrome, MELAS, MERRF, Freidrich’s ataxia Fatty Acid Oxidation Disorder MCAD, LCHAD, VLCAD Ketogenesis Mitoch HMG CoA Synthase Defic Classification Disorders of Complex/Large Molecules Lysosomal Storage Disorders MPS Sphingolipidoses GM1, GM2 type 1 (Tay-Sahcs), GM2 type 2 (Sandhoff), Fabry, Farber, Gaucher, Niemann-Pick, Krabbe, metachromatic leukodystrophy Oligosaccharidoses Mucolipidosis Peroxisomal Disorders Zellwegers, neonatal adrenoleukodystrophy, infantile Refsum Single Peroxisomal Enzyme Disorder X-linked ALD, Refsum disease (phytanoyl CoA hydroxylase deficiency) Congenital Disorder of Glycosylation CDG type 1a Inborn Errors of Cholesteral Synthesis Smith-Lemli-Opitz syndrome Purine and Pyrimidine Metabolism Classification Neurotransmitter metabolism and vitamins/other disorder Glycine and serine metabolism Pterin and biogenic amine metabolism Gamma-aminobutyrate metabolism Other (e.g., pyridoxine-dependent or folinic acid-dependent seizures, sulfite oxidase deficiency)  Categories of IEM Disorders caused by energy failure Glycogen (GSD), fatty acid (FAOD), mitochondrial Decompensations with stress or increased energy demand Disorders of amino acid metabolism Tend to present in infancy as lethargy or vomiting Disorders of carbohydrate metabolism Lysosomal storage disorders Peroxisomal biogenesis disorders White matter disorders Grey matter disorders Presentation Chronic Presentation Acute Presentation Developmental delay (emergency) Failure to thrive Developmental regression Organomegaly Recurrent vomiting Neuropathy Acute liver, heart failure Big molecule Severe hypotonia, rhabdomyolysis Small molecule Metabolic Emergencies Metabolic Acidosis Low pH, low bicarb Seen with amino acid disorders, organic acid disorders May be present in disorders of pyruvate metabolism, mitochondrial disorders and disorders of carbohydrate metabolism Usually with increased anion gap resulting from presence of abnormal metabolites, such as ketoacids, lactic acid or organic acid that is unable to be metabolized Respiratory Alkalosis High pH, low pCO2 Suggestive of urea cycle defects, can also see with organic acid disorders Caused by tachypnea, which is induced from hyperammonemia Hyperammonemia Characteristic feature of urea cycle defects and organic acidemia, however can still be normal in these patients if not acutely ill Can also occur in amino acid disorders (lysinuric protein intolerance) and fatty acid oxidation Can be seen in mitochondrial disorders if have hepatic dysfunction Hypoglycemia Occurs in disorders of ketogenesis, FAOD (MCAD), GSDs, disorders of gluconeogesis and hereditary fructose intolerance Metabolic Emergencies Work Up Initial Specialized tests Urine organic acids (organic acid CBCdiff and FAOD) Glucose, Ur, Cr Urine reducing substances Urinalysis, myoglobin, urine for ABG ketones Ammonia (no tourniquet, Serum amino acids (amino acid on ice, etc.) and urea cycle) Lactate and pyruvate (on ice) AST, ALT, bili Acylcarnitine profile, free and total Coags carnitine (FAOD and organic acid) Lactate dehydrogenase, aldolase, creatine kinase and urine myoglobin (for McArdles, VLCAD, CPT) CSF – Amino acids, lactate, protein Metabolic Emergencies Management ABCs Fluid resuscitation – normal saline Treat hypoglycemia +/- bicarb for acidosis Avoid parenteral nutrition until known disorder if possible Administer IV dextrose (with electrolytes) – provides energy and prevents catabolism. Infusion rate of 8-10mg/kg/min of dextrose should be adequate to suppress catabolism Significant hyperammonemia may require hemodialysis and/or medications L-carnitine, L-arginine  help with urea cycle Sodium benzoate  scavenger Phenylbutryate  scavenger Treat cerebral edema as normal, +/- hemofiltration to remove offending metabolites Disorders caused by energy failure Glycogen storage disorders Fatty acid oxidation defects Mitochondrial disorders Glycogen Storage Disease Glycogen Storage Disease Energy failure with fasting and exercise GSD Type II (Pompe disease), AR Truly is lysosomal storage disorder (GAA gene, acid maltase deficiency) Infantile: severe hypotonia and cardiomyopathy, hepatomegaly Childhood: progressive weakness, very high CK (mimic DMD) Ix: muscle bx (+)glycogen storage (-)acid maltase No hypoglycemia; EMG myopathic Tx: enzyme replacement, high protein, low carb diet Glucose-6-phosphatase deficiency (GSD Type I) Recurrent hypoglycemic seizures, truncal obesity, hepatomegaly, “doll face” Subcut fat in cheeks, buttocks and breast; xanthomas on skin Glycogen Storage Disease GSD Type V (McArdle’s disease), AR PYGM gene, phosphorylase deficiency Adolescence: cramps + fatigue shortly after exercise High CK, rhabdomyoglobinuria Second-wind phenomenon: improvement in exercise tolerance after slowing down due to increased cardiac output, switch to glucose and free fatty acids for muscle metabolism Out-of-wind phenomenon: glucose intake before exercise exacerbates sx due to metabolic block occurring below level of glucose into glycolysis Ix: Failure of normal lactate peak during forearm ischemic lactate test; EMG (fibrillations, positive sharps, myotonic discharges), elevated CK Tx: oral sucrose, low to moderate exercise Fatty acid oxidation defects  Fatty acid oxidation defects AR inheritance Defect in transporting fatty acids into mitochondria or intramitochondrial beta- oxidation Defect metabolizing long chains (14-18) = VLCAD, LCHAD Defect metabolizing medium chains (6-8) = MCAD Defect metabolizing short chains (4) = SCAD Triggered by prolonged fasting (3-4hr neonate, 10-12hr adult) or significant stress (illness, surgery) or low intensity exercise Ix: hypoketotic hypoglycemia, mild-mod hyperammonemia, acylcarnitine levels Sensitive organs: brain, heart, muscles, liver Tx: no fasting, IV dextrose (acute), carnitine (secondary deficiency) Includes: Carnitine transporter deficiencies (CPT) MCAD Glutaric acidemia type II Carnitine transporter deficiencies Muscle weakness & cardiomyopathy from renal loss  results in complete carnitine depletion CPT1 deficiency: Reye-like syndrome – progressive encephalopathy, seizures from hypoglycemia, hepatomegaly, mod hyperammonemia, elevated liver enzymes No cardiac involvement Positive acylcarnitines CPT2 deficiency: Infantile (liver) form: hepatomegaly, liver failure, cardiomegaly, seizures, hypoketotic hypoglycemia Adult (muscle) form Other FAODs MCAD deficiency Acute presentation of vomiting/seizure/progressive encephalopathy after fasting or stress May result in sudden infant death Glutaric acidemia type II Affects both FAO and AA metabolism Reye-like syndrome: seizures, progressive neurodegeneration Mitochondrial Disorders Mitochondrial disorders Genetic defect may be nuclear or mitochondrial DNA Heterogenous clinical picture: multisystem involvement of high-energy systems Brain, eyes, ears (SNHL), nerves (pain, areflexia, dysautonomia), muscle, heart, liver (hypoglycemia, liver failure), kidneys, endocrine (diabetes) Ix: lactate high at rest, lactate:pyruvate >25, classic MRI, muscle bx Tx: levocarnitine, B2, B1, CoQ, biotin, folate  Leigh Syndrome Subacute necrotizing encephalomyelopathy mtDNA or nDNA – most AR Clinical: infancy/early childhood Regression after viral infection, ataxia, dystonia/chorea, nystagmus, seizures, lactic acidosis, hypertrophic cardiomyopathy Ix: MRI: b/l symmetric necrotizing lesions with spongy changes and microcysts in basal ganglia, thalamus, brainstem, spinal cord MRS: lactate peak, elevated choline, reduced NAA Lactic acidosis during episodes Tx: supportive MELAS Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes Multisystem & progressive Mutation in mtDNA.: maternal inheritance, heteroplasmy due to valuable mutation load Gene: MT-TL1 (among others) Clinical: Stroke with encephalopathy, headaches, GI issues, FTT, cardiac dysfunction, blindness, deafness Vague stroke presentation: aphasia, headache, encephalopathy, seizure, weakness MELAS: Ix & Management MRI: crosses cerebral vascular territories, usually posterior parietal/occipital lobes Lactic acidosis in blood/CSF; muscle bx = RRF Treatment: arginine in acute phase (500mg/kg peds, 10g/m2 body surface area adults) Arginine 150-300mg/kg/day divided TID CoQ10, L-carnitine Annual ophtho, cardio, audio Mitochondrial Disorders mtDNA Disorders nDNA Disorders Disorders of amino acid metabolism Aminoacidopathies Organic aciduriras Urea cycle defects Aminoacidopathies Symptoms result from accumulation of substance that cannot be metabolized Usually present after interval of good health (can be hours to years) followed by metabolic decompensation with poor feeding and lethargy Can become unwell after catabolic insult (fasting, infection, surgery) or have certain food loads (excessive carbs, etc) Features Irritability/sleepiness Difficulty feeding, vomiting, FTT Seizures Jaundice Most are screened in NMS Phenylketonuria (PKU) Classic PKU: phenylalanine (high)  (phenylalanine hydroxylase)PAH  tyrosine (low) Elevated blood and urine phenylalanine and metabolites (phenylacetate) Excessive phenylalanine interferes with brain growth, myelination and neurotransmitter syntehsis AR, most caused by gene encoding PAH, chromosome 12q24.1 PKU Clinical Progressive symptoms of cognitive delay, microcephaly, spasticity, seizures, rash in 1st year of life. Musty odor in infancy  regression by 2 years of age Behavioural disturbance: hyperactivity, ADHD, aggression (often present even if treated) Seizures, aethetosis Blonde hair, pale skin, blue eyes (low/no melanin); eczema-like rash Now with NMS treated patients are essentially asymptomatic Ix: QAA elevated phenylalanine, MRI can haveT2 signal in periventricular and parieto-occipital WM Tx: Diet – protein-formula without phenylalanine (need small amount to function) Nonketotic hyperglycinemia Aka Glycine encephalopathy (.: also NT disorder) Main cause of early myoclonic encephalopathy GLDC gene, AR Clinical features Persistent hiccups in utero Neonatal period: encephalopathy, hypotonia, apneas, myoclonic jerks Seizures, dyskinesias, profound ID Mild episodic childhood variant (rare) Regression, delirium, chorea during febrile illness NHK: Ix & management Investigations High CSF glycine (30x normal) CSF:plasma glycine ratio >0.08 MRI: agenesis of CC, progressive atrophy, delayed myelination, can have incr DWI signal in symmetric WM MRS: elevated glycine peak (+high creatine and lactate) EEG: burst suppression, multifocal seizures Tx: sodium benzoate (lowers plasma glycine), dextromethorphan (NMDA-R antagonist; helps with sz control), ketogenic diet VPA contraindicated NKH: Imaging  Classic homocystinemia Causes Genetic: AR, MTHFR Vitamin deficiency: folate, B6, B12 CKD – decreased removal/impaired metabolism Smoking Clinical features Tall thin, marfanoid, pectus excavatum/carniatum Ectopia lentis Seizures, psych disorders, developmental delay Thromboembolic events like stroke, MI, PE Ix: Deficiency of cystathionine beta synthase High serum/urine homocysteine – can cause prothrombotic state Test B12, folate, B6 Tx: pyridoxine + folic acid (nutritional deficiencies) Cobalamin  Others MSUD: classic = neonate with poor feeding, ketonuria, lethargy – coma, seizures Accumulation of leucine, isoleucine, valine, AR Intermittent form: attacks of ataxia + cerebral edema, triggered by illness/stress Ix: elevated branched-chain AA (leucine isoleucine valine) during attack, hyperammonemia, ketoacidosis, WM changes Hartnup disease SLC6A19 – encodes for amino acid transporter Episodic cerebellar ataxia and pellagra-like rash Tyrosinemia – causes coagulopathy (liver failure) leading to neurologic crises (painful neuropathy), stroke Organic acid disorders  Organic Aciduria AR inheritance Neonates w/ poor feeding, vomiting, lethargy to coma, sepsis Ix: HAG metabolic acidosis*, ketosis, hyperammonemia Propionic Aciduria: cognitive disability, seizures, basal ganglia strokes, late complications = cardiomyopathy, pancreatitis, movement disorders Methylmalonic Aciduria: severe acidosis and hyperammonemia in neonate  seizures, spasticity, behavioural problem, stroke, renal failure +/- B12 responsive MRI brain: bilateral globus pallidus infarction Biotinidase deficiency: hearing loss, optic atrophy, alopecia, eczematous skin rash, ataxia Picked up on NMS, treat with biotin Glutaric Aciduria Type I AR, neurodegenerative Clinical features: Onset 13-18mo with encephalopathic crises during acute illness (dystonia, spasticity, cognitive dysfunction) Focal striatal necrosis MRI brain: macrocephaly, frontotemporal atrophy, basal ganglia lesions, bat-wing sylvian fissure May see intraretinal hemorrhage and SDH from rupture of bridging veins.: can look like NAI Ix: MRI, UOA (elevated glutaric acid) Tx: Dietary restrictions of lysine, carnitine and riboflavin supplementation Glutaric Aciduria Type II Affects both FAO and AA metabolism Clinical features: Sudden metabolic crisis in infancy: hypoglycemia, vomiting Reye-like syndrome: seizures, progressive neurodegeneration May be associated with sweaty feet odor, polycystic kidneys Urea Cycle Disorders  Urine: ↓orotic acid = CPS1 or NAGS def Serum: ↓ arginine ↓citrulline = CPS 1, NAGS or OTC def Urine: ↑orotic acid = OTC def Serum: Absent ASA ↑↑citrulline Urine: arginine N to ↑ = citrin def arginine ↓ = ASS def Urine: ↑homocitruline Serum: ↑ornithine ↓citrulline Serum: Present ASA = ORNT1 def ↑ or N citrulline = ASL def Serum: ↑ ↑ arginine = ARG def **Present in first few days of life due to ammonia **Present older with subtle accumulation. Causes neuro signs and liver cerebral edema, FTT,  Urea Cycle Defects Inability to convert toxic ammonia into urea Mostly AR pattern of inheritance (except OTC – X-linked) Acute crisis of encephalopathy  seizures  coma and death May see strokes and cerebral edema Vomiting, protein aversion, temperature changes, adults - psych Ix: Hyperammonemia without acidosis provoked by catabolic state  cerebral edema E.g., neonates soon after initiating protein feeds Permanent neuro deficits can occur after single crisis Tx: Stop protein intake, ++glucose +lipids (promote anabolism), sodium benzoate (scavenger) Consider dialysis Liver transplant is curative! But will not reverse neurological damage OTC (ornithine transcarbamylase) Deficiency X-linked (females symptomatic carriers 10%), most common urea cycle disorder Clinical features Male neonate with irritability, feeding dysfunction, lethargy May have seizures leading to coma if untreated Late presentation: headaches, vomiting, bizarre behaviour, seizures May be milder in females due to X-inactivation Triggered by protein load or catabolic post-partum state Ix: High ammonia and urine orotic acid, low serum citrulline, arginine (QAA) Tx: Sodium benzoate (scavenger), arginine, dialysis, restriction of protein, liver transplant Other Urea Cycle Defects CPS1 deficiency: normal urine orotic acid Argininemia: mild elevation in ammonia Progressive spasticity, weakness, tremor, regression, seizures Can have spastic CP Hyperornithemia-hyperammonemia-homocitrullinemia (HHH) syndrome Develops in older children Spasticity, coagulation defects Cerebral Creatine Deficiency Syndromes Inborn errors of creatine metabolism GAMT deficiency (AR) AGAT deficiency (AR) Disorders of creatine biosynthesis CRTR deficiency (X-linked) Disorders of creatine transporter Clinical features Seizures, ID, behaviour issues (autism, self mutilation), movement disorders (chorea/dystonia) Ix: urine creatine/creatinine, MRS (absence of creatine peak), genetic testing Rx: oral creatine in biosynthesis disorders Disorders of Carbohydrate Metabolism Galactosemia Congenital disorders of glycosylation Lafora body disease Galactosemia Mutations in GALK, GALT or GALE genes Neonates with vomiting and poor feeding Jaundice, hepatomegaly, cataracts if untreated Often develop e.coli sepsis Treatment: avoid galactose and fructose Congenital Disorders of Glycosylation Infants or children with combination of: Classically combination of liver, gastrointestinal and coagulation disturbances FTT, hypotonia Stroke-like episodes Blotting/bleeding Hypotonia Cerebellar Hypoplasia Peripheral neuropathy Inverted nipples Hypogonadism Ix: transferring electrophoresis Lafora Body Disease AR inheritance Mid teens: myoclonic epilepsy and rapid neurologic decline Lafora bodies: dark with acid Schiff, lighter outer halo Lysosomal Storage Diseases Mucopolysaccaridoses Sphingolipidoses Fabry disease Neimann-Pick NCL Lysosomal storage diseases Lysosomes break down and recycle complex substrates including glycosaminoglycans, sphingolipids, glycogen and proteins Accumulation of large carb-lipid complexes Classification based on primary stored substance: Sphingolipids (gangliosidosis, MLD, Krabbe, Fabry’s, Gaucher, Farber’s, NM-A/B) Mucopolysaccharidoses (Hunter, Hurler, Sanfilippo, Morquio) Lipidosis Mucolipiosis Glycogen (pompe, danon) Cholesteral (NP-C, Wolman) Clinical features: Progressive dysmorphisms Organomegaly Psychiatric symptoms WM disease  Mucopolysaccharidosis Mostly AR Coarse facial features (storage of glycosaminoglycans in soft tissue), short stature, dysostosis multiplex (progressive skeletal dysplasia, bullet-shaped phalanges, flattening if vertebral bodies), hepatosplenomegaly MPS I: Hurler – ID, corneal clouding, cardiac disease MPS II: Hunter – no corneal clouding, aggressive, papules on thighs [X-LINKED RECESSIVE] MPS III: Sanfilippo – ID, behaviour/speech problems, progressive CNS degeneration MPS IV: Morquio – odontoid hypoplasia Ix: Urine MPS + enzyme assays: leukocytes or fibroblasts MR brain: dilated perivascular spaces (Virchow-Robbins) Locations: periventricular WM, corpus callosum, basal ganglia, subcortical white matter, thalami or brainstem Radial orientation from subependymal region toward the cortex Tx: enzyme replacement therapy MPS Rads Axial T2 MRI Cystic fusiform dilated perivascular space (black arrow) Sagittal T1 MRI Marked perivascular space enlargement (arrowhead), corpus callosum (black arrow), and subcortical white matter (white arrow) Sphingolipidoses  Sphingolipidoses GM2 gangliosidosis aka Tay-Sachs (type alpha) HEXA gene, AR – [Ashkenazi jewish] Infants with excessive startle, cherry red spot, regression  encephalopathy, spasticity, seizures, blindness, megalencephaly Late onset GM2 gangliosidosis: childhood and adults with cog/behaviour decline, spasticity, seizures NO cherry red spot Caused by hexosaminidase A deficiency Ix: Absent Hexosaminidase A with normal/elevated HexoB GM2 gangliosidosis aka Sandhoff’s disease (type beta) Like Tay-Sachs + hepartosplenomegaly + bony deformities Caused by deficiency of both hexosaminidase A and B Ix: low HexoA and HexoB Hallmarks of gangliosidoses Disease Manifestation Regular symptoms/signs Facultative symptoms/signs GM1- Dysmorphic face, severe dysostosis, Cherry-red macular spot, seizures, gangliosidosi Infantile hepatomegaly, hypotonia  spasticity, splenomegaly, joint contractures, s visual failure, foam cells in bone marrow vacuolated blood lymphocytes Juvenile By 4 years or later: dysarthria, dystonia Slight intellectual impairment As in juvenile disease, but with more Adult Psychosis insidious onset Loss of head/trunk control GM2- Cherry-red macular spot, high startle gangliosidosi Infantile response to noise, hypotonia by 1 year, s epilepsy, tetraparesis with some spasticity, dementia, blindness Onset by 3 to 6 years, dysarthria, loss of Seizures, irritability, psychiatric signs, Juvenile/ speech, spastic paraparesis, cerebellar denervation muscle atrophy (EMG), subacute ataxia, mental deterioration areflexia, cherry red macular spot Clumsiness, LMN disease, denervation Adult Psychosis muscle atrophy, cerebellar ataxia Fabry Disease GLA gene, x-linked recessive Alpha-galactosidase A deficiency, sphingolipid Clinical features: young adult male Brain – stroke Ganglion cells of dorsal root - neuropathic pain (acroparasthesias – ass with physical activity, fever, cold) Heart – arrhythmias, hypertrophic CM Kidneys – ESRD Skin – angiokeratomas around lips, abdomen or genitalia Hearing loss, corneal opacities Dx: blood spot screening test for enzyme analysis, confirmed by leukocyte/plasma enzyme measurement Treatment: enzyme replacement therapy Gaucher’s Disease AR, deficiency of lysosomal enzyme glucocerebrosidase Clinical: Osteopenia, osteosclerosis, bone pain/crises Hepatosplenomegaly, interstitial lung disease, pulm HTN, heme malignancy, delayed growth/puberty GDS 1 – non-neuropathic GDS2 – congenital icthyosis, oculomotor dysfunction, hypertonia, opisthotonos, seizures GSD3 – progressive dementia, ataxia, myoclonus, seizures Ix: Enzyme analysis, bone marrow has Gaucher cells (macrophages filled with lipid material) Tx: enzyme replacement therapy Neimann-Pick disorders Disorder of impaired cholesterol esterification NPA: cherry red spot, opisthotonos, hyperreflexia, hepatomegaly Infant with FTT, lung disease NPC: [NPC1 & NPC2 gene AR] Severe liver/lung disease, upgaze palsy, ataxia, apraxia, seizures, dystonia, dementia Childhood onset: cerebellar ataxia, vertical supranuclear gaze palsy, dystonia, seizures, spasticity, gelastic cateplexy Adolescent onset: progressive learning difficulties and/or behavioural dysfunction Adult onset: psychosis, affective disorders Tx: cholesterol lowering agents (statins), Miglustat (decrease lipid storage) Neuronal Ceroid Lipofuscinosis (NCL) Group of disorders characterized by progressive cognitive and motor deterioration, seizures, vision loss and early death Most common cause of inherited childhood neurodegenerative disease Initially classified by age of onset, now by genetic etiology (multiple chromosomes) Infantile NCL (onset 6-24mo): delay, myoclonic jerks, progressive impairment Late infantile (2-4yr): seizures followed by cognitive decline, ataxia, spasticity, movement disorders, visual impairment to blindness CLN2 gene Juvenile aka ”Batten disease” (5-12yr): visual failure  academic decline, hallucinations, myoclonic and tonic-clonic seizures, ataxia and rigidity Death within 10-15yr CLN3 gene (most common) NCL NCL Skin bx: curvilinear or granular osmiophilic deposits, fingerprint profiles EEG: encephalopathy with myoclonic seizures, large spike + slow-wave with photic stimulation MRI: progressive atrophy, decreased T2 signal intensity in thalami, thinning of corpus callosum, may have diffuse WM changes MRS: reduced NAA Eventual loss of SSEPs Tx: avoid Dilantin and Tegretol Benzos for seizure/spasticity, trihexyphenidate for dystonia Cerliponase alfa (ERT; intrathecal) Other Lysosomal Disorders Farber – granulomatous tissue infiltration by foamy macrophages Swollen & deformed joints, hoarse cry, nodules on fingers Krabbe – AR, GALC gene, galctosylceramidase Irritability, psychomotor regression, visual impairment, spasticity Low galctosylceramidase activity; MRI tigroid Metachromatic Leukodystrophy – AR, ARSA gene, arylsulfatase A Spasticity, spasms, peripheral neuropathy MRI: butterfly pattern, tigroid Peroxisomal Disorders Zellweger syndrome Peroxisomal Disorders Two major categories: Disorder of peroxisomal biogenesis (defect of assembly) Zellweger, refsum, neonatal adrenoleukodytrophy Single-enzyme disorder X-linked adrenoleukodystrophy  Zellweger syndrome Aka cerebrohepatorenal syndrome aka infantile Refsum PEX1 gene, AR inheritance Clinical features: Neonatal hypotonia, high forehead, wide fontanelle Hepatomegaly, hyporeflexia, renal cysts, patellar stippling Develop intractable seizures, liver dysfunction, SNHL Pigmentary retinal abnormalities MRI brain: hypomyelination + neuronal migrational defects Centrosylvian pachygyria with lateral polymicrogyria Ix: Elevated VLCFA, phytanic acid Peroxisomes degrade VLCFA Refsum Disease AR, PHYH gene (90%) or PEX7 gene Clinical features: Infancy: Zellweger Hypotonia, GDD Retinitis pigmentosa.: develop vision loss SNHL, ataxia, peripheral neuropathy Ichthyosis Cardiac conduction defects Vit-K responsive bleeding (sign of liver dysfunction) Ix: NCS: demyelinating Serum phytanic acid high Tx: Low phytanic acid diet X-linked Adrenoleukodystrophy ABCD1 gene, Xp28 Peroxisomal disorder, VLCFA View leukodystrophy lecture Others Smith-Lemli-Opitz DHCR7 gene  7-dehydrocholesterol reductase mutation, AR Impaired cholesterol synthesis Clinical features: Microcephaly, ptosis, short upturned nose, self-injurious behaviour Cleft lip/palate, syndactyly of toes, polydactyly of hands Hirschsprung, abnormal genitalia, cardiac malformations Ix: high 7DHC, low cholesterol MRI can show: Holoprosencephaly ACC Frontal hypoplasia Cerebellar hypoplasia Dandy-walker malformation  Lesch-Nyhan X-linked recessive, HGPRT1 gene Purine metabolism defect.: develop hyperuricemia Clinical features: Hypotonia and GDD  choreoathetosis, dystonia, self- mutilating behaviour  renal failure, gouty arthritis  Menkes syndrome X-linked recessive, ATP7A gene Disorder of copper transport resulting in low serum copper and ceruloplasmin – deficient absorption in GI tract Presents after normal development for 2-3mo followed by developmental delay, regression, myoclonic seizures in response to stimulation, dysautonomia, hypotonia Kinky hair, skin laxity, sagging jowls (skin beneath neck), light pigmentation Tortuous cerebral vessels: ischemic strokes, subdural hematoma Death before age 3 MRI: defective myelination, atrophy, MRI – corkscrew appearance of vessels Low copper and ceruloplasmin levels Tx: SubQ copper histidine or chopper chloride Wilson’s Disease AR inheritance, ATP7B gene Disorder of copper transporting ATPase resulting in impaired binding to ceruloplasmin.: low serum copper & ceruloplasmin, high urinary copper Accumulation of copper in liver (liver disease, hepatomegaly, bronze skin), brain (tremor, chorea, dystonia, dysarthria, psych symptoms, cognitive dysfunction), eyes (KF rings) MRI: symmetric basal ganglia, thalamus, brainstem lesions (T2 bright) Tx: copper chelator penicillamine Porphyria Altered activities in heme biosynthetic pathway Most AD with low penetrance, some AR or XL Acute intermittent porphyria (AIP) – HMBS pathogenic variant Neurovisceral sx triggered by drugs (cytochrome p450-inducers), progesterone, fasting, stress Attacks of abdo pain, red/brown urine, muscle weakness, convulsions, hyponatremia Paresis common extreme pain, psych sx, altered LOC TRIAD: abdo pain, CNS dysfunction, peripheral neuropathy in young adult female Ix: urinary porphobilinogen; MRI can have PRES picture Tx: hemin; glucose  Cerebrotendinous Xanthomatosis (CTX) Lipid storage disorder – deficiency of sterol 27-hydroxylase resulting in cholestanol and cholesterol accumulation CYP27A1, AR Clinical: Neuro: pyramidal and cerebellar findings, dystonia, atypical parkinsonism, peripheral neuropathy, seizures, onset 20-30s ID, behavioural changes, aggression, depression MRI: hyperintensities in deep grey/supratentorial WM, microcalcifications in dentate, enlarged Virchow-robin spaces High cholestanol, normal to low cholesterol Tx: chenodeoxycholic acid (CDCA), CoQ10 for weakness Glut-1 deficiency Syndrome AR, SLCA1 gene Clinical features: Infantile onset epileptic encephalopathy associated with a low CSF glucose concentration (mean 30mg/dL) Refractory seizures of all clinical types (focal, generalized, myoclonic) Neurodevelopmental impairment of variable severity and acquired microcephaly Ix: Low CSF glucose (cannot transport across BBB), ratio