Spingolipidoses Step 1 Board Review 4/27/17 Joseph G. Hacia, Ph.D. hacia@hsc.usc.edu

Recommended textbook for all Biochemistry Lectures Year 2 students often use this textbook for USMLE Step 1 Exam review Recommends the use of textbooks Donovan Roy Director of Academic Support Services Keck School of Medicine

Brain lipids and carbohydrates fatlisa.files.wordpress.com/2013/10/r-fat-food-brain-large570.jpg

Lecture overview Introduce a class of lysomosomal storage disorders called sphingolipidoses Discuss enzyme deficiencies and substrate accumulation Diagnose sphingolipidoses based on classic presenting features in the clinic 4

Lysosomal storage disorders (LSDs) plasma membrane endo- somes F-actin phagosome secretory vesicle lyso- some Lysosomal storage disorders (LSDs) Physiology 25: 102-115 (2010) microtubules golgi endoplasmic reticulum

Subset of lysosomal storage disorders that can affect the central nervous system Sphingolipidoses (accumulate sphingolipids) Fabry disease X-linked (recessive) Gaucher disease Autosomal recessive Krabbe disease Metachromatic leukodystrophy Niemann-Pick disease Tay-Sachs disease About 60 different kinds of LSDs are known CNS is NOT affected in every person with a LSD Fabry and Krabbe disease, and metachromatic leukodystrophy are classified as leukodystrophies Fabry disease mnenomic: special “F” X-linked inheritance

What are sphingolipids? (Biochemist) Lippincott Figure 17.18 All are derived from ceramide All have sphingosine group Some are phospholipids Some are glycolipids Sphingomyelin: a sphingophospholipid Lippincott Figure 17.4

No structures on exam! sphingomyelin sulfatide cerebroside ganglioside simple sugar oligosaccharide sialic acid phospho- head group sphingomyelin sulfatide cerebroside ganglioside HO SO 3 sulfate

Examples of their importance to the CNS Sphingomyelin constitute 2–15% of total organ phospholipid membrane structure, signal transduction, and apoptosis Inherited deficiencies in glucocerebroside catabolism are found in about 7% of Parkinson’s disease cases Sulfatides constitute 4% of total myelin lipids and regulate oligodendrodyte differentiation, survival, and stability Gangliosides represent about 1% of all brain lipids mediate axon–myelin cell–cell interactions enhance long-term axon–myelin stability https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540844/#bib24 http://www.sciencedirect.com/science/article/pii/S0300908401013086

Representative sphingolipidoses 1 Fabry disease Gaucher disease Sandhoff disease Farber disease Krabbe disease Metachromatic leukodystrophy Niemann-Pick disease Tay-Sachs 4 3 5 2 6 Lippincott Figure 17.20

LA Metro Rail Map 1 3 4 2 5 6 www.drodd.com/images16/los-angeles-metro-map12.jpg

Lippincott Figure 17.20 1

sphingomyelin cerebroside sulfatide ganglioside simple sugar simple oligosaccharide sulfate phospho- head group HO SO 3 sialic acid sphingomyelin cerebroside sulfatide ganglioside

Tay-Sachs disease: Genetics Autosomal recessive disorder caused by HEXA gene mutations Also called hexosaminidase A deficiency Incidence varies according to ancestry 1in 360,000 birth in North America 1 in 3,600 Ashkenazi Jewish births (two founder mutations) Also French-Canadians, Louisiana Cajuns, Pennsylvania Amish www.ubooks.pub/Books/B0/E10R1010/MAIN/images/image036.jpg

Classic clinical findings for Tay-Sachs disease Symptoms begin to manifest between ages three and six months progressive weakness and loss of motor skills decreased attentiveness and increased startle response Typical findings on physical examination: cherry-red spot of the fovea centralis of the macula normal-sized liver and spleen generalized muscular hypotonia Later manifestations: progressive neuro- degeneration, seizures, blindness, spasticity Lifespan usually less than 4 years of age www.ntsad.org www.linkedin.com/in/suekahn/

Tay-Sachs disease: Real-life Subtype Clinical manifestations Acute infantile discussed last slide Juvenile (subacute) later onset and survival into late childhood or adolescence Chronic and adult-onset progressive dystonia, spinocerebellar degeneration, motor neuron disease with muscle weakness and fasciculations, and/or psychosis You are only responsible for acute infantile for exam

Lippincott Figure 17.20 2

sphingomyelin sulfatide cerebroside ganglioside simple sugar oligosaccharide sialic acid phospho- head group sphingomyelin sulfatide cerebroside ganglioside HO SO 3 sulfate

Niemann-Pick Type A disease: Genetics Autosomal recessive disorder caused by SMPD1 gene mutations Also called acid sphingomyelinase (ASM) deficiency Estimated incidence is about 1 in 250,000 births in US Potential higher incidence in some populations 1:40,000 births in the Ashkenazi-Jewish population 1:45,000 births in the Chilean population predicted nnpdf.org Lippincott Figure 17.12

Classic clinical findings for Niemann-Pick Type A First symptom is hepatosplenomegaly, usually by 3 months, and most children survive less than 3 years Psychomotor development progresses no further than the 12- month level, afterwards neurologic deterioration Interstitial lung disease leads to respiratory infections and failure Classic manifestations found on examination cherry-red spot of the macula of the retina foam cells (sphingomyelin-laden macrophages) 24th Annual NNPDF Family Support & Medical Conference www.flickr.com/photos/146187384@N02/29073982295/in/album-72157672680328195/

Niemann-Pick disease: Real-life Subtype Clinical manifestations A discussed in prior slide B present with hepatosplenomegaly with progressive hypersplenism & stable liver dysfunction, gradual deterioration in pulmonary function, osteopenia, & atherogenic lipid profile; progressive and/or significant neurologic manifestations infrequent; adult survival possible C (subtypes C1 and C2) presents in infants to adults, but classically occurs in mid-to-late childhood with the onset of ataxia and dementia; dystonia and seizures common; death usually occurs in the late 20’s or 30’s from aspiration pneumonia; adults likely to present with dementia or psychiatric symptoms. You are only responsible for subtype A for exam

Cherry-red spot on the macula Tay-Sachs Niemann-Pick www.ncbi.nlm.nih.gov/pmc/articles/PMC3864975/figure/F3/

Classic foam cells in Niemann-Pick Type A Lippincott’s Illustrated Reviews: Biochemistry 6th Edition Figure 17.13

Lippincott Figure 17.20 3

sphingomyelin cerebroside sulfatide globoside simple sugar simple oligosaccharide sulfate phospho- head group HO SO 3 H no sialic acid group sphingomyelin cerebroside sulfatide globoside

Fabry disease: Genetics X-linked disorder (also called alpha-galactosidase A deficiency) caused by GLA gene mutations Hemizygous males: typically earlier onset and more severe Heterozygous females: typically later onset and milder Incidence is 1:40,000 to 1:60,000 males in North America* Found in all ethnic, racial, and demographic groups Italian population: 1:3,000 incidence with an 11:1 ratio of persons with the later-onset/classic phenotypes Taiwan-Chinese population: cardiac-variant form of disease found in 1:1,600 newborn males www.fabrydisease.org

Classic clinical findings for Fabry disease Usually involves males with childhood or adolescent onset Suspected in males and females with the following features: Periodic crises of severe pain in the extremities Vascular cutaneous lesions (angiokeratomas) Characteristic corneal and lenticular opacities Unexplained stroke Unexplained left ventricular hypertrophy Renal insufficiency of unknown etiology Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in the third to fifth decade Cardiac and/or cerebrovascular disease is a major cause of morbidity and mortality Median survival: 50 - 55 years for men and 70 years for women

Pediatric Neurology 64: 10-20 (2016) Angiokeratoma on the back of a male patient T1-weighted MRI of the brain of a 28-year-old man with a history of repeated strokes Cornea verticillata in a female patient

Fabry disease: Real-life Classic Renal variant Cardiac Age of onset 4-8 yrs >25 yrs >40 yrs Average age of death 41 yrs >60 yrs Manifestation angiokeratoma ++ - acroparesthesia +/- hypohidrosis/anhidrosis corneal/lenticular opacity + cardiac disease LVH/ischemia LV cardiomyopathy cerebrovascular disease TIA/stroke renal disease ESRD proteinuria enzyme activity <1% >1% ESRD: end-stage renal disease LVH: left ventricular hypertrophy TIA: transient ischemic attack www.ncbi.nlm.nih.gov/books/NBK1292/

www.fabrydisease.org/

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www.fabrydisease.org/

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Lippincott Figure 17.20 3

sphingomyelin cerebroside sulfatide ganglioside simple sugar simple oligosaccharide sulfate phospho- head group HO SO 3 sialic acid sphingomyelin cerebroside sulfatide ganglioside

Gaucher disease type 1 (GD1): Genetics Autosomal recessive disorder caused by GBA gene mutations Also called glucocerebrosidase deficiency Incidence varies according to ancestry 1:40,000 to 1:100,000 people in North America 1:500 to 1:1000 of Ashkenazi Jewish ancestry Four common mutations in people with type 1 Gaucher disease 90% of mutant alleles in Ashkenazi-Jewish individuals 50% - 60% of mutant alleles in non-Jewish individuals www.gaucherdisease.org www.gaucherdisease.org/mystatus/

Classic clinical findings for Gaucher disease type 1 Many adult patients undergo bone marrow testing before receiving a diagnosis to rule out blood cancers pediatrician may notice an enlarged spleen, bleeding problems and low platelets without diagnosing GD1 Classic clinical characteristics bone disease: osteopenia, osteoporosis bone pain/crisis bone infarction or avascular necrosis hepatosplenomegaly anemia and thrombocytopenia lung disease absence of primary CNS disease

glucocerebroside-laden macrophages from bone marrow Lippincott’s Illustrated Reviews: Biochemistry 6th Edition Figure 17.19 Lippincott’s Illustrated Reviews: Biochemistry 6th Edition Figure 17.19 glucocerebroside-laden macrophages from bone marrow

Multisystem involvement can manifest at any age www.physio-pedia.com/images/2/26/Multi_system_inolvement.JPG

Gaucher disease: Real-life Subtype Onset CNS Bone Other Type 1 variable, usually diagnosed after childhood No Yes splenomegaly,hepatomegaly, cytopenia, pulmonary disease Type 2 onset <2 yrs of age; lifespan 2-4 yrs of age hepatomegaly, splenomegaly, cytopenia, pulmonary disease dermatologic changes Type 3  onset <2 yrs of age; survival until 30s-40 Type 1 comprises 95% of Gaucher disease cases Perinatal-lethal form and cardiovascular forms also exist

5 6 Lippincott Figure 17.20

sphingomyelin cerebroside sulfatide ganglioside simple sugar simple oligosaccharide sulfate phospho- head group HO SO 3 sialic acid sphingomyelin cerebroside sulfatide ganglioside

Metachromatic leukodystrophy: Genetics Autosomal recessive disorder caused by ARSA gene mutations Also called arylsulfatase A deficiency Incidence varies according to ancestry Between 1 in 40,000 and 1 in 160,000 in different populations Populations with higher prevalence of consanguineous marriages 1 in 75 in Jewish Habbanite community in Israel 1 in 8,000 in Israeli Arabs 1 in 2,500 for western portion of U.S. Navajo Nation www.mldfoundation .org blog.mldfoundation.org/wp-content/uploads/2015/05/MLD-Family-Conference%E2%84%A2-Pittsburgh-2014-no-watermark.jpg

Classic clinical finding for metachromatic leukodystrophy Onset is between ages one and two years. Typical presenting findings: weakness, hypotonia, clumsiness, frequent falls, toe walking, and slurred speech Later signs include inability to stand, difficulty with speech, deterioration of mental function, increased muscle tone, arm and leg pain, seizures, compromised vision and hearing, and peripheral neuropathy Paralysis and blindness often reported with a prognosis of 1-2 years, although that usually extends to 5-7 years after diagnosis Brown metachromasia in peripheral nerve. Sulfatide deposits stain pink with H&E. With acid cresyl violet, they take on a brown color (brown metachromasia). neuropathology-web.org/chapter10/chapter10bLSDs.html

You are only responsible for late-infantile for exam MLD: Real-life Subtype Clinical manifestations Late-infantile MLD 50%-60% of cases Onset: 1-2 years of age Weakness, hypotonia, clumsiness, frequent falls, toe walking, & slurred speech.  Juvenile MLD 20%-30% of cases Onset: 4-14 years of age Decline in school performance and emergence of behavioral problems, followed by clumsiness, gait problems, slurred speech, incontinence. Seizures may occur. Adult MLD 15%-20% of cases Onset: 14-60 years of age School or job performance, personality changes, substance abuse, emotional lability; weakness and loss of coordination progressing to spasticity and incontinence; seizures; peripheral neuropathy common.  You are only responsible for late-infantile for exam

6 Lippincott Figure 17.20

sphingomyelin cerebroside sulfatide ganglioside simple sugar simple oligosaccharide sulfate phospho- head group HO SO 3 sialic acid sphingomyelin cerebroside sulfatide ganglioside

Krabbe disease: Genetics Autosomal recessive disorder caused by GALC gene mutations Also called galactocerebrosidase deficiency and globoid cell leukodystrophy Pan-ethnic: occurs in 1 in 100,000 births in US and Europe Some populations noted with higher incidence rates 1 in 100-150 births in Druze community in Northern Israel and two Moslem Arab villages located near Jerusalem 1 in 6 carrier frequency in those communities Hunter James Kelley 2/14/97 – 8/05/05 www.huntershope.org/site/PageServer

Classic clinical findings for Krabbe disease Infants are normal for first few months of life, but show extreme irritability, spasticity, and developmental delay before six months Psychomotor regression progresses to a decerebrate state with no voluntary movement and average age of death at 13 months Clinical presentation includes any and all of the following: Muscle hypertonicity Progressive neurologic deterioration Peripheral neuropathy Evidence of white matter disease on neuroimaging Elevation of cerebrospinal fluid (CSF) protein concentration www.facebook.com/pg/HuntersHope/photos/?tab=album&album_id=10153657914497021

“Some galactosylceramide in the form of filamentous or tubular inclusions accumulates in brain macrophages which are transformed into large, often multinucleated, PAS-positive, globoid cells” neuropathology-web.org/chapter10/chapter10bLSDs.html

Krabbe disease: Real-life Subtype Clinical manifestations Infantile form 85% - 90% of cases Onset: Few months after birth Lifespan: 13 months Stage I: irritability, stiffness, arrest of motor & mental development, temperature elevation without infection; hypersensitive to stimuli, cries frequently Stage II: rapid, severe motor & mental deterioration Stage III: infant is blind with no voluntary movement, no contact with his/her surroundings Late-onset forms 10-15% of cases Onset: 6 months to seventh decade Lifespan: varies can be clinically normal until almost any age when symptoms of weakness, vision loss, and intellectual regression become evident; variable clinical course, even among siblings You are only responsible for ‘infantile’ for exam

Typical biochemistry Step 1 board question Four sentence clinical vignette You must diagnose disease What enzymatic activity is defective? What molecules accumulate or are deficient? What is the risk of having a child with this disorder?

Telling these diseases apart on USMLE Exams Disease Initial clinical presentation Hallmark ‘classic’ clinical characteristics Tay-Sachs Between 3-6 months of age Cherry-red macula, progressive evidence of neurodegeneration: seizures, blindness, spasticity, death usually before 4 years  Niemann-Pick Usually 3 months Cherry-red macula, insidious onset of ataxia, dementia, enlargement of liver or spleen Metachromatic leukodystrophy Between 1-2 years of age Weakness, hypotonia, clumsiness, toe walking, & slurred speech; vision deterioration Krabbe Around a few months of age Irritability, spasticity, & developmental delay <6 months. Weakness, vision loss, and intellectual regression; macrophages accumulate galactolipids (globoid cells)

Telling these diseases apart on USMLE Exams Disease Initial clinical presentation Hallmark ‘classic’ clinical characteristics Fabry Between 4-8 years of age angiokeratoma, peripheral neuropathy, diminished sweating, cornea opacity later on: cardiac, cerebrovascular and renal disease Gaucher Variable: usually after childhood bone disease; hepato-splenomegaly, anemia and thrombocytopenia, lung disease, absence of primary CNS disease, lipid-laden macrophages

After diagnosis, what do you need to recall? Condition Enzyme Accumulated substrate Fabry alpha-galactosidase ceramide trihexoside globotriaosylceramide Gaucher glucocerebrosidase beta-glucosidase glucocerebrosides Krabbe galactocerebrosidase galactocerebrosides psychosine Metachromatic leukodystrophy arylsulfatase A sulfatides Niemann-Pick Type A sphingomyelinase sphingomyelin Tay-Sachs hexosaminidase A GM2 gangliosides

http://www.usmle.org/step-1/#question-formats

http://www.usmle.org/step-1/#question-formats (Farber disease) (Fabry disease) (Gaucher disease) (Tay-Sachs disease) (Hurler disease) (Niemann-Pick disease) http://www.usmle.org/step-1/#question-formats

Never forget the families affected by these devastating diseases Most important of all! Never forget the families affected by these devastating diseases ulf.org 2013 GFPD Memorial Balloon Release