Download 2014-2015 Metabolic

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
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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
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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
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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
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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
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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
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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
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Included in 2012 as an answer choice
Cystathionine beta synthase deficiency
AR
Typically present as adults
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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
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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
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Lysosomal Storage Disorders
• Examples
– Niemann Pick
– Krabbe
– Fabry
– Metachromatic Leukodystrophy
– Gaucher
– GM1 gangliosidosis
– GM2 gangliosidosis (Tay-Sachs)
– Neuronal Ceroid lipofuscinoses
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Niemann-Pick Disease
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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
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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
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Tay Sachs Disease
• Deficiency of:
– Hexosaminadase A
• Asked once in 2009
• AR
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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)
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Case
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24 year old man
Mildly elevated creatinine
Complains of painful distal sensory loss
Frequent fainting when standing
Erectile dysfunction
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Case
• Angiokeratoma
– Painless papules
predominating on the
lower body
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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)
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Gaucher
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Incorrect answer in 2010 and 2014
Deficiency of the glucocerebrosidase
AR
HSM, thrombocytopenia, anemia, bleeding,
osteopenia
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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
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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.
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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
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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
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Metachromatic Leukodystrophy
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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
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Metachromatic Leukodystrophy
2014
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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
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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
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Glucose and Glycogen Storage
Disorders
• Galactosemia
• Larora Body
• Glycogen Storage Disorders
– Pompe
– McArdles
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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
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Lafora (Body) Disease
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Asked in 2010, 2013 (pathology)
AR
Mid-teen onset
Myoclonic epilepsy
Rapid neurocognitive deterioration
Supportive care
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Lafora (Body) Disease
• Rounded, targetoid inclusions.
• Often found in cerebral cortex
• Demonstrated in virtually every tissue (i.e. skin
biopsy)
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Glycogen Storage Disorders
• Pompe (GSD II)
– Asked every year
– Acid maltase (alpha 1-4 glucosidase) deficiency
– Presents at about 2 months with
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FTT
Cardiomegaly
Hepatomegaly
Progressive weakness
Macroglossia with tongue fasciculations
Hypotonia
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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
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Glycogen Storage Disorders
• McArdle Disease (GSD V)
– Myophosphorylase deficiency
– Adolescence
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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
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Other
• Lesch-Nyhan
– Deficiency of hypoxanthine-guanine
phosphoribosyltransferase
– Dystonia/chorea by 12 months
– Self-injurious behavior by 2-4 years
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Leukodystrophies
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Leukodystrophies
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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
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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
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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
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Alexander Disease
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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
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Alexander Disease
• Associated with megalencephaly (along with
Canavan)
• MRI:
– Involves U-fibers (as does Canavan)
– Frontal predominence
– Contrast enhances (as does adrenoleukodystrophy)
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Pelizaeus-Merzbacher Disease
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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)
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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
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Leukodystrophy Review
• Blah blah, baby, head circumference >97%
• MRS shows elevated NAA spike
• What is it?
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Leukodystrophy Review
• Blah blah, baby, head circumference >97%
• MRS shows elevated NAA spike
• What is it?
• Canavan Disease
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Leukodystrophy Review
• U-fibers involved?
• Choices:
A: Alexander disease
B: Wilson’s disease
C: Canavan disease
D: Krabbe disease
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Leukodystrophy Review
• U-fibers involved?
– No
• Choices:
A: Alexander disease
B: Wilson’s disease
C: Canavan disease
D: Krabbe disease
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Leukodystrophy Review
• U-fibers involved?
– No
• Choices:
A: Alexander disease
B: Wilson’s disease
C: Canavan disease
D: Krabbe disease
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