Download METABOLIC DISEASES

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?