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METABOLIC DISEASES: Storage disorders I. GSD Type I II Glycogen storage diseases: many considered as metabolic myopathies Enzyme Defect Glucose-6-phosphatase Acid maltase (1,4 glucosidase) Eponym Von Gierke Pompe Distinctions Liver, Kidney ERT therapy Clinical Manifestations Hypoglycemic seizures Infantile: neonatal hypotonia, macroglossia, cardiomegaly, hepatomegaly; usually death by age 2 due to CR failure or aspiration PNA Adult: 20s-30s age of presentation: youngerfatigue; older- leg and trunk weakness; may present or later develop respiratory failure Path, labs, buzz words Path: PAS + membrane bound vacuoles Type II die by age 2 Pumps dz- defective pump Plumps dz- Plump heart, liver, and tongue EMG: paraspinal myotonia without clinical myotonia Intracranial aneurysms due to glycogen deposition- often basilar Increased CPK; normal ischemic exercise test Adult AM: Aneurysms and Myotonia *Also considered a LSD III IV V Debranching enzyme Transglucosidase Muscle phosphorylase Cori-Forbes Andersen McArdle, Ch 11 q12-13.2 VI VII Liver phosphorylase Muscle phosphofructokinase Hers Tarui VIII IX X Phosphorylase kinase Phosphoglycerate kinase Lactic Dehydrogenase *All involve muscle except I and VI * All are AR except for IX *II and IV involve mainly brain Mainly muscle XLR Fatigue, cramps, myoglobinuria “second wind phenomenon”- reduced level of exercise after brief rest period following onset of muscle pain or cramps Primarily affects distal muscles EMG usually normal Forearm ischemic lactate test is abnl: lack a rise in lactate Presents in childhood: exercise induced myoglobinuria and exercise intolerance: cramps and fatigue; sx resolve with rest No second wind phenomenon; abnormal forearm ischemic test; Path: subsarcolemmal glycogen depositsblebs II. Lysosomal Storage Disorders: A. Mucopolysaccharidoses MPSs result from abnormal degradation of glycosaminoglycans such as dermatan sulfate, keratan sulfate, heparan sulfate, and chondroitin sulfate resulting in organ accumulation and eventual dysfunction MPS Type I-H I-H/S Enzyme Defect Alpha-L-iduronidase Alpha-L-iduronidase Eponym Hurler HurlerScheie Scheie Hunter San Filippo Morquio I-S II III IV Alpha-L-iduronidase Iduronate sulfatase 4 Types: Galactose-6-sulfatase VI Arylsulfatase- B MarateauxLamy VII Hyaluronidase Sly Distinctions Liver, Kidney XLR Keratan sulfate Dermatan sulfate Intelligence MR MR ETC Normal MR MR Normal Milder form of Hurler Normal MR Most common short trunk dwarfism and a skeletal dysplasia (spondyloepiphyseal) Severe skeletal abnormalities, Cardiac involvement is related to aortic and mitral valvular dysfunction from thickened calcified stenotic valves. glycosaminoglycan excretion and granulocytes showing striking coarse metachromatic granules. All are AR except for Hunter (II); Corneal clouding is common, except for Hunter. Most all have coarse facial features and dysostosis multiplex; hepatomegaly common. Can have obstructive hydrocephalus or cervical cord compression as a result of skeletal deformities at the base of the brain -Diagnosis: Glycosaminoglycan fragments are generated by alternative pathways and are excreted in the urine. Simple enzyme assays are available for the diagnosis of MPS from fibroblast, leukocyte, or serum samples. Electron microscopy: zebra bodies B. Sphingolipidoses, etc Disease Enzyme Defect Lipid storage disorders Fabrys Alpha-galactosidase A AKA CM Buzz words Fabrys: As: -alpha-galactosidase A -acroparesthesias -autonomic dysfunction -anhydrosis -Abdominal pain -arrhythmia -angiokeratomas FABRY: -Foot Edema -A’s -Belly pain, burning extremities -Renal Failure -eYe findings: corneal deposits Cerise means cherry in French: ceramidase deficiency causes Cherry-red spot XLR, Ch X q22 Globotriaosylceramide -Rash, angiokeratomas- dark red/purple papules in groin and umbilical area; -Autonomic dysfunction: hypohydrosis, decreased tears and saliva, impotence, GI dysmotility; diarrhea, abdominal pain -Small fiber neuropathy: lancinating pains in distal extremities: acroparesthesia; worsened by fever, hot weather, exercise -Hand and foot edema -ERT available First few weeks to months: hoarseness, subcutaneous nodules, macular cherry-red spots, progressive arthropathy Neuro: hypotonia, weakness, dev delay I: non neuropathic- most common form, organomegaly only II: acute neuropathic form; visceral organomegaly and dev delay; trismus, strabismus, opisthotonus, spasticity; death usually by 2 III: Chronic neuropathic form First decade: cognitive deterioration, sz, rigidity, ataxia. Horizontal supranuclear gaze palsy; HSM, interstitial lung disease Presents with FTT, persistent neonatal jaundice, hepatomegaly, developmental delay. Progress to regression, rigidity, sz Death by age 3-5 Pulmonary infiltrates, LAD, abdominal distension *Cherry red spot Purely visceral form; Farber’s Ceramidase Lipogranulomatosis AR Ceramide esp in joints Gaucher’s Beta-glucosidase (glucocerebrosidase); Saposin C (rarely) AR Gaucher cells: PAS + histiocytes containing lipid Glucosyceramide/ glucocerebroside accumulation Niemann Pick A Sphingomyelinase Classic infantile neuronopathic form AR Nieman Pick B Sphingomyelinase Visceral form AR ERT for Types I and III; Path: gaucher cells- look like crumpled tissue paper Ashkenazi Jewish NP type A: -Adenopathy -Abdominal distention -Ashkenazi Jewish Path: foamy histiocytes (contain lipid) NP types A and B: -FTT, progressive HSM, developmental regression, ataxia, hypotonia, cherry red Nieman Pick C NPC1 gene: Ch 18q1112; NPC2 gene: Ch 14 q Sphingomyelin, abnormal cholesterol transport Neonates: jaundice and hepatomegaly; infants: hypotonia and developmental delay Classic form: 3-8 yrs with clumsiness, which progresses to ataxia; dystonia -vertical supranuclear gaze palsy early- downward first; then Dysarthria, dystonia, dysphagia, dementia -can also see cataplexy, choreoathetosis, sz spots NPC: abnormal Cholesteral transport; Cataplexy Leukodystrophies- white matter Krabbe Galacosyl ceramide beta galactosidase (galactocerebroside): GALC gene Chromosome 14q31 AR “globose cell leukodystrophy Infantile form: 3-6 mos: irritability and rigidity; may feed poorly with unexplained fevers. Later: seizures, spasticity, optic atrophy, blindness, deafness, PMR -Progressive demyelinating peripheral neuropathy DTR are lost, but bilateral Babinskis present EMG: decreased NCV CSF protein elevated CT: hyperdense BG, thalami, CR, brainstem, cerebellum Path: globoid cells -central and peripheral myelin MRI- spares U fibers MLD Aryl-sulfatase A AR, Ch 22 0r multiple sulfatase deficiency Gangliosidoses- affect gray matter (a type of sphingolipidosis) AR GM-1 Beta-galactosidase Galactosylsulfatide (cerbroside sulfatide) –Late infantile (40% of the patients with MLD) *Gait disorder and strabismus early in 2nd year of life *Gradual impairment of speech, spasticity, intellectual deterioration §Death usually within 4 yrs of onset of symptoms –Juvenile (40%) *Neurological symptoms appear between 5 and 7 years, progress slowly *Often present with declining school function –Adult (20%) *Organic mental syndrome with progressive corticospinal, corticobulbar, cerebellar or extrapyramidal signs Sandhoff Hexosaminidase A and B, Chromosome 5`q13 GM-2 gangliosidosis Infantile, late infantile, and juvenile Sz, cherry red spots (infantile), sz, pyramidal signs, spasticity, encephalopathy -associated with mild HSM, death by age 3, often due to respiratory infection Tay-Sachs Hexosaminidase A deficiency GM-2 gangliosidosis Mainly Ashkenazi Jewish; cherry red spots, macrocephaly, progressive blindness Rx: SCTx, BMTx MRI: diffuse demyelination with sparing of U fibers, CN enhancement; Urine sulfatides -central and peripheral myelin affected Cherry red spots *gray and white matter affected Picture sandbag under their shirt, making abdomen bigger, so HSM Gray matter disease: Tay rhymes with gray -Classic infantile: 2- 6mos: progressive weakness, motor regression, decreased social interaction, blindness, sz, spasticity, encephalopathy NCL Disorders of grey matter NCL 1: Infantile Palmitoyl protein thioesterase NCL 2: Late Infantile NCL 3: Juvenile Tripeptidyl peptidase NCL 4: Adult Transmembrane protein Battenin Lipopigment accumulation Seizures, dementia, vision loss Path: ballooned neurons with foamy cytoplasm and displaced neurons NCL rhymes with “not see well” -8 total types but 4 main ones *most common LSD? *sz, blindness, developmental regression, Santauvori Ch1 p32: HagburgSantauvori Ch. 11 p15 6 mos- 2 years: ataxia, myoclonic sz, psychomotor regression, progressive visual loss, microcephaly Late infantile form (bielchowsky-jansky) Biekchowsky-Jansy Ch. 16 CLN BattenSpielmeyerVogt/ Kufs Age 2-8; visual sx Batten’s Cerebellar and extrapyramidal signs Kufs Type I: not dysmorphic, 2-4th decade with gait abn, myoclonus, visual disturbances; decreased color vision, decreased VA; ataxia, hyperreflexia, Type II: congenital or infantile: also with cherry red spots Hurler’s phenotype, severe gingival hyperplasia AKA: Sialidosis “cherry red spot-myoclonus” syndrome Glycoproteinoses- LSDs that affect the glycoproteins Mucolipidosis alpha-neuraminidase AR type I (ML I) Mucolipidosis II AR Mucolipidosis III (pseudoHurler polydystrophy AR MPS and mucolipids More severe, but clinically similar to Hurler’s III. Peroxisomal disorders Enzyme/organs genetics GFAP AR accumulation CM Tests, buzz words Dysmorphic, weak, hypotonic, poor feeders, seizures, retinal degeneration, hearing deficits MRI- deficiency of myelin Labs: VLFA, pipecolic acid, phytanic acid elevated Peroxisomal biogenesis DO Neonatal ALD Eye: Brushfield’s spots, cataracts, glaucoma, corneal clouding Similar to neonatal ALD -hepatomegaly, sensorineural deafness, retinal degeneration -anosmia -MR Prominent forehead, epicanthal folds, large fontanelle, cataract, brushfeld spots, renal cysts, hepatomegaly Weak, hypotonic, developmental delay, Infantile Refsum Disease Zellweger Peroxisomal biosynthesis Cerebrohepatorenal Multiple genes/PEX. AR XR: calcific stippling of patellae and hips MRI: migration defects: polymicrogyria, heterotopias, pachygyria Labs: increased bili, iron VLCFA, CSF protein X linked ALD ATP-binding cassette transporter superfamily of proteins AMNadrenomyeloneuropathy Childhood onset: normal development until 4-8 yrs: progressive neurodegeneration, with behavior and cognitive defects, spasticity, impaired vision and hearing; adrenal insufficiency Slowly progressive paraparesis in adulthood: with long tract signs, UMN signs, distal sensory loss MRI: inflammatory myelinopathy is more posterior: parieto-occipital and corpus callosum; Night blindness in first or second decade of life. -Retinitis pigmentosa, ataxia, anosmia, deafness,, icthyiosis, diabetes -chronic hypertrophic SM neuropathy with onion bulbs -Skeletal defects ie epipjyseal dysplasia -CSF protein very high -cardiac failure may result in death Tx: diet low in phytanic acid REFSUM: R-rough skin (ichthyosis, retinitis pigmentosa) E-can’t hear F- falls, phytanic acid S- smell is lost U-unsteady gait M-myelin lost Lab: elevated ACTH Not Peroxisomal but good to mention Childhood Onset RefsumClassic form Phytanoyl-CoA hydrolase Phytanic acid 1. Which storage diseases affect gray matter? White matter? Both? a. MLD b. NCL c. Krabbe d. Tay-Sachs e. Nieman Pick 2. Match the disease with the enzyme Tay Sach MLD Nieman Pick Pompe’s Krabbe’s McCardle Fabry Hexosaminidase A Myophosphorylase alpha galactosidase A Hexosaminidase A and B Aryl-sulfatase A Galactocerebrosidase acid maltase 3. Which LSD(?s) affect central and peripheral white Matter? Spare the subcortical U fibers? 4. Identify clinical features with disease a. Night blindness, icthyiosis b. Spares subcortical U fibers c. lancinating pains in distal extremities: acroparesthesia; worsened by fever, hot weather, exercise d. neonatal hypotonia, macroglossia, cardiomegaly, hepatomegaly 5. Distinguishing characteristic between Tay-Sachs and Sandhoffs 6. Two distinguishing characteristics of the MPS Hunter’s 7. Which leukodystrophies are peroxisomal? Lysosomal?