Inherited Metabolic Diseases Flashcards
number of mitochondrial genes
37
homoplasmy
the presence of either completely normal or completely mutant mitochondrial DNA
of the five complexes that make up the respiratory chain, _____________ or complex ____, is the one most often disordered and its deficient function gives rise to lactic acidoses
cytochrome-c oxidase
complex IV
The first definite indication of disordered nervous system function is likely to be the occurrence of
seizures
three most frequently identified hereditary metabolic diseases that do not become clinically manifest in the neonatal period
phenylketonuria
hyperphenylalaninemia
congenital hypothyroidism
vitamin-responsive aminoacidopathy
autosomal recessive
early onset of convulsions, sometimes in utero
failure to thrive, hypertonia-hyperkinesia, irritability
tremulous movements
exagerated auditory startle
psychomotor retardation
increased excretion of xanthurenic acid in response to tryptophan load
decreased levels of pyridoxal-5-phosphate and GABA in brain
mutation: ALDH7A1 gene
Pyridoxine-dependent seizures
treatment: 50-100mg of Vitamin B6 suppresses the seizure state and daily doses of 40mg permit normal development
some patients with increased concentrations of phenylalanine in the neonatal period are unresponsive to measures that lower phenylalanine
if not treated promptly will lead to seizures - myoclonic and grand mal types, poor level of responsiveness, generalized hypotonia
swallowing difficulty
normal levels of phenylalanine hydroxylase enzymes
there is a lack of cofactor for phenylalanine hydroxylase (cofactor of phenylalanine hydroxylase)
Biopterin deficiency
treatment: tetrahydrobiopterin in a dosage of 7.5mg/kg/d in combination with a low-phenylalanine diet
dx: urine pterins
Autosomal recessive
defect in Galactose-1-phosphate uridyl transferase (GALT)
the enzyme which catalyzes the conversion of galactose-1 phosphate to uridine diphosphate galactose
onset after first days of life, after ingestion of milk
vomiting and diarrhea and followed by failure to thrive
drowsiness, inattention, hypotonia,
fontanels may bulge, the liver and slpeen enlarge, skin becomes yellow, anemia
dxs: elevated blood galactose level
low glucose
galactosuria
deficiency of GALT in red and white blood cells, liver cells
Galactosemia
treatment: dietary, milk substitues
Beta Galactosidase deficiency
GM1 gangliosidosis
N-acetylhexosaminidase alpha subunit deficiency
Tay Sachs Disease
N-acetylhexosaminidase beta subunit deficiency
Sandhoff disease
GM2 activator deficiency
Acitivator Deficiency
arylsulfatase (sulfatidase), sulfatide activator (saposin B) deficiency
Metachromatic Leukodystrophy
galactocerebrosidase deficiency
Krabbe
Alpha galactosidase A deficiency
Fabry disease
Glucocerebrosidase deficiency
Gaucher disease
sphingomyelinase deficiency
Type A and B Niemann Pick Disease
Ceramidase deficiency
Farber Disease
Alpha Galactosidase B deficiency
Schindler Disease
deficiency of alpha keto acid dehydrogenase
resulting in accumulation of branched-chain amino acids leucine, isoleucine, valine
autosomal recessive
Maple Syrup Urine Disease
urine test for MSUD
2,4 dinitrophenylhydrazine DNPH
seizures, tremulousness, drowsiness occur with blood sugar levels less than
mature infant:
premature:
mature less than 30mg/dL
premature 20mg/dL
hallmark of all the hereditary metabolic diseases
psychosensorimotor regression
autosomal recessive
disease becomes apparent in the first weeks and months of life - almost always on the 4th month
regression of motor activity and an abnormal startle to acoustic stimuli, listlessness, irritability, poor reactions to visual stimuli
hypotonia then later spasticity
degeneration of macular cells - cherry red spot
Tay Sachs Disease
deficiency of N-acetylhexosaminidase a subunit
accumulation of GM2 gangliosides
brain is large
loss of neurons
remaining nerve cells are distended with glycolipid
autosomal recessive
before 6 months, frequently before 3
oculomotor apraxia, strabismus, rapid loss of head control, ability to roll over and sit, apathy, irritability, frequent crying, difficulty in sucking and swallowing
increase in serum acid phosphatase, characteristic histiocytes in marrow smears and liver and spleen biopsies
deficiency of glucocerebrosidase
accumulation of glucocerebroside
Infantile Gaucher Disease Type II
most patients do not survive beyond 1 year
90 percent not beyond 2 years
autosomal recessive
mutation in ASAH1
The onset is in the first weeks of life, with a hoarse cry because of fixation of laryngeal cartilage, respiratory distress, and sensitivity of the joints, followed by characteristic periarticular and subcutaneous swellings and progressive arthropathy, leading to ankylosis
ceramidase deficiency
Farber disease
Lipogranulomatosis
spongy degeneration of the brain
autosomal recessive
onset first neonatal weeks to first 3 months of life
rapid psychomotor function regression, loss of sight and optic atrophy, lethargy, difficulty sucking, irritability, reduced motor activity, hypotonia followed by spasticity, macrocephaly
sensorineural hearing loss, seizures
blond hair and fair complexion opposed to dark. haired sibling
increased urinary NAA
deficiency of aminoacylase II
CT imaging: attenuation of cerebral and cerebellar white matter with enlarged brain
Spongy Degeneration of Infancy
Canavan Disease
pathognomonic sign of wilson disease or hepatolenticular degeneration
Kayser-Fleischer rings
initial event in Wilson disease
deposition of copper in the liver leading to an acute or chronic hepatopathy and eventually to multilobular cirrhosis and splenomegaly
T/F
wilson disease.
The first neurologic manifestations are most often extrapyramidal with proclivity to affect the oropharyngeal musculature.
true
T/F
Wilson disease.
The kayser-fleischer rings are virtually always present once the neurologic signs become manifest.
true
T/F
The parkinsonian features of wilson disease are responsive to levodopa.
false
lab findings in Wilson Disease
levels of serum ceruloplasmin, serum copper, urinary copper excretion
low serum ceruloplasmin
low serum copper
increased urinary copper excretion
treatment for wilson disease
- reduction of dietary copper to 1mg/d
avoidance of copper rich foods: liver, mushrooms, cocoa, chocolate, nuts, shellfish - administration of copper chelating agents, D-penicillamine 1-3g/d, or triethylene tetramine, ammonium tetrathiomolybdate
another substitute is zinc - blocks intestinal absorption of copper
zinc acetate 100 to 150mg daily in 3-4 divided doses
X-linked recessive
hereditary choreoathetosis and hyperuricemia
onset: 3-6months
initially hypotonia then hypertonia, aggressive and compulsive
delayed speech
moderately severe mental retardation
gouty tophi, gouty arthropathy
deficiency in enzyme HPRT, hypoxanthine-guanine-phosphoribosyl transferase
HPRT gene in X chromosome
Lesch-Nyhan syndrome
treatment for Lesch-Nyhan Syndrome
allopurinol
what cAn be given to suppress self-mutilation in Lesch-Nyhan
haloperidol fluphenazine (prolixin)
aka as pigmentary degenration of globus pallidus
autosomal recessive
defect in gene encoding PANK2
affectes CST and has extrapyramidal signs
patient becomes inarticulate, unable go walk
CT hypodense lenticular nuclei
MRI eye of the tiger, T2 rim of pallidum appears intensely black - iron deposition - with a small white area on the medial part
neuropath: brown pigmentation of the globus pallidus, substantia nigra, red nucleus
no treatment
Neurodegeneration with Brain Iron Accumulation
formerly Hallervorden-Spatz Disease, PANK mutation
pantothenate kinase
Fahr Disease
idiopathic form of calcificatiom of the basal ganglia and cerebellum in which choreoathetosis and rigidity are prominent features
may also present: parkinsonian and athetosis, bilateral
some with normal intellect
normal serum Calcium
Osteopetrosis
familial occure ce of calcification in caudate and lenticular nuclei, thalami, and frontal lobe white matter in association with osteopetrosis (marble bones)
basic abnormality: deficiency in carbonic anhydrase II
striking odor of stale perspiration
sweaty foot syndrome
isovaleric acidemia
what compound accounts for the maple syrup odor
a-hydroxybutyric acid
neuropathologic findings in MSUD
interstitial edema
pallor and loss of myelin and gliosis of parts of the cerebral white matter
autosomal recessive
onset of type A: 3-9 months
marked enlargement of spleen, liver, and lymph nodes with infiltration of lungs
loss of spontaneous movements, lack of interest in the environment, axial hypotonia with bilateral corticospinal signs, blindness, amaurotic nystagmus, macular cherry red spot vacuolated histiocytes (foam cells) in the bone marrow, vacuolated blood lymphocytes deficiency in sphingomyelinase
Infantile Niemann Pick Disease
autosomal recessive
onset before 6th month
generalized rigidity, loss of head diminished alertness, frequent vomiting, irritability, and bout of inexplicable crying, spasms induced by stimulation, increasing muscular tone, opisthotonic recurvation of neck and trunk
myocolonus in response to auditory stimuli
mots die by the end of the firts yr, and survival beyond 2 years is unusual
deficient galactocerebrosidase
accumulation of galactocereroside metabolite psychosine - leads to detsruction of oligodendrocytes and depletion of lipids in WM
Krabbe disease
precipitated by infection or fever
progressive encephalopathy
rapid deterioration
irritability, loss of vision, ataxia, seizures, coma
symmetric leukodystrophy with progressive disappearance of WM and replacement by CSf or gliosis
mutations in elF2B?
Vanishing White Matter Disease
mutations in ASAH1
horase cry because of fixation of laryngeal cartilage, respiratory distress, sensitivity of the joints
periarticular and subcutaneous swellings and progressive arthropathy
severe psychomotor delay
Farber Disease, Ceramidase Deficiency
X-linked
affected gene encode proteolipid protein
onset: 1st months of life,
abnormal movements of eye, jerk nystagmus, hypoetric saccades, spastic weakness of limbs, optic atrophy, ataxia of limb, intention tremor, choreiform movements, dysarthria, cerebellar ataxia, mental retardation
absence of oligodendrocytes and myelin fibers
Pelizaeus-Merzbacher Disease (PLP1 Mutation)
most frequent of the aminoacidurias
autosomal recessive
impairment of psychomotor development can usually be recognized in the latter part of the first year when expected performance lags
hyperactivity, aggressivity, self-injurious behavior, clumsy gait, fine tremor, poor coordination, odd posturings, seizures
blue-eyed, fair skin color, skin is rough and dry, subject to eczema
musty body odor
high levels of serum phenylalanine and of phenylpyruvic acid in the blood, CSF and urine
deficiency of enzyme PA hydroxylase
Phenylketonuria
screening test for PKU
Guthrie (ferric chloride) test
addition of ferric chloride to urine yields an emerald green color (transient) fades in 20-40 mins
name the condition that when tested with ferric chloride in urine yields the color below
green-brown color:
navy-blue:
purple:
green-brown color: histidinemia
navy-blue: MSUD
purple: propionic and methylmalonic acidemia
imaging in PKU
pigmented nuclei (substantia nigra, locus ceruleus, dorsal vagal motor) fail to acquire dark coloration because of a block in the production of neuromelanin
dermatologic aminoacidopathy
mild to moderate Mental retardation
self-mutilation, incoordination of limb movements, Language defects are prominent
1st-2nd yr of life: lacrimation, photophobia, redness of eyes
neovascularization of eyes, opacification
palmar and plantar keratosis with hyperhidrosis and parin -result of reaction to deposits of crystalline tyrosine
elevated tyrosine in urine and blood
deficiency of enzyme: fumarylacetoacetate hydrolase
hereditary tyrosinemia
richner-hanhart disease
progressive infantile encephalopathy
fluctuating extrapyramidal symptoms in combination with ocular and vegetative symptoms
L-dopa causes some improvement in motor symptoms
Tyrosine hydroxylase deficiency
autosomal recessive
babies are normal at birth
onset: late infancy or early childhood
intermittent red, scaly rash over the face, neck, hands, and legs resembling pellagra
episodic personality disorder in the form of emotional lability, uncontrolled temper, confusional hallucinatory psychosis, episodic cerebellar ataxia, spasticity, vertigo, nystagmus, ptosis, diplopia
ATTACKS: triggered by sunlight, emotional stress, sulfonamide drugs and last for 2 weeks
transport error of neutral amino acids across renal tubules with excretion of greatly increased amounts of amino acids in urine and feces
Hartnup Disease
SLC6A19 Mutation
tx: nicotinamide 50-300mg/d
L-tryptophan ethyl ester 20mg/kg tid
Persistent cerebellar ataxias of childhood in which a metabolic fault has been demonstrated
Refsum disease Abetalipoproteinemia (Bassen-Kornzweig syndrome) Ataxia-telangiectasia Galactosemia Friedreich ataxia
lysosomal (sphingolipid) storage disease
abnormality is mutation of the gene for enzyme arylsulfatase A which prevents the conversion of sulfatide to cerebroside (a major component of myelin)
autosomal recessive
Metachromatic Leukodystrophy
Arylsulfatase Deifciency
onset: first to fourth years of life
progressive impairment of motor function (gait disorder, spasticity) in combination with reduced output of speech and mental regression
signs of mental regression
impairment of vision
nystagmus, intention tremor, dysarthria, dysphagia, droolinh grayish degeneration of maculae
Metachromatic Leukodystrophy
widespread degeneration of myelinated fibers in the cerebrum, cerebellum, spinal cord, peripheral nerves
presence of metachromatic granules in glia cells and engorged macrophages is characteristic and enables the diagnosis to be made form a biopsy of a peripheral nerve
stored material:sulfatide stains brow orange in PAS
Metachormatic Leukodystrophy
increase in sulfatide
absence of arylsulfatase A
Metachormatic Leukodystrophy
Neuroaxonal Dystrophy
Degeneration PLA26 Mutation
psychomotor deterioration (loss of ability to sit, stand, and speak) marked hypotonia but brisk reflexes and Babinski signs and progressive blindness with optic atrophy but normal retinae
patho: eosinophilic spheroids of swollen axoplasm in the posterior columns and nuclei of Goll and Burdach and in the Clarke column, substantia nigra, subthalamic nuclei, central nuclei of brainstem and cerebral cortex
splenomegaly, Gaucher cells , deficient activity of glucocerebrosidase
gaucher disease
subacute or chronic neurovisceral storage disease
splenomegaly
dementia, dysarthria, ataxia, choreoathetosis, paralysis of horizontal and vertical gaze
syndrome of “sea-blue histtiocyte”
liver spleen and bone marrow contain histiocytes with sea-blue granules
Late Infantile - Early Childhood
Niemann Pick Disease
MPS 1
mental retardation, skeletal abnormalities
gargoyle fascies
large head with synostosis of longitudinal suture
broad hands, short stubby fingers
conductive deafness
CST signs
protuberan abdoen, hernias, enlarged liver and spleen, valvular heart, corneal opacities
accumulation of dermatan and heparan sulfate (glycosaminoglycans)
absence of a-L0iduronidase
Hurler Disease
Tx: enzyme replacement
hematopoietic stem cell bone marrow transplantation
deficiency in a-L-iduronidase
glycosaminoglycan: dermatan sulfate, heparan sulfate
Hurler
MPS I
deficiency in iduronate sulfatase
GAG: dermatan sulfate, heparan sulfate
Hunter
MPS II
deficiency in Heparan N-sulfatase
GAG: heparan sulfate
Sanfilippo
MPS III
deficiency in galactose 6-sulfatase
GAG: keratan sulfate, chondroitinn 6-sulfate
Morquio
MPS IV
deficiency in N-acetylgalactosamine, 4-sulfatase (arylsulfatase B)
GAG: dermatan sulfate
Maroyeaux-Lamy
MPS VI
deficiency in B-glucuronidase
GAG: dermatan sulfate, heparan sulfate, chondroitin 4-sulfate
Sly
MPS VII
X-linked
milder than Hurler
Hunter
MPS II
Strokes in association with inherited metabolic diseases
consider the ffg:
homocystinuria
fabry disease
sulfite oxidase deficiency
autosomal recessive
simulates Marfan
tall, slender, great length of libs, scoliosis, arachnodactyly, thin and weak muscles, knock knees, highly arched feet, hyphosis
sparse blond, brittle hair, malar flush
livedo reticularis
mental retardation
mutations in CBS that codes for cystathionine beta-synthase
elevated homocysteine in blood and CSF
infarcts in brain are related to thrombotic and embolic arterial occlusion
homocystinuria
elevation of lactate concentration in blood and CSF is a feature of mitochondrial disorders
These elevations are most prominent :
after exercise
infection
fever
alcohol ingestion
T/F
Diagnosis of MELAS or Leigh syndrome cannot be excluded in the presence of normal levels of lactate even after provocation by exercise.
True
p995
epilepsy
deafness
developmental delay with ragged red muscle fibers
MERFF
myoclonic epilepsy with ragged red fibers
ptosis and symmetrical ophthalmoplegia
mitochondrial disorder
Progressive External Ophthalmoplegia
migraine-like headaches
recurrent small strokes preceding seizures
MELAS
Mitochondrial Encephalomyopathy
Lactic Acidosis
Stroke-Like Episodes
Ophthlamoplegia
retinitis pigmentosa
polyneuropathy
deafness
Kearns-Sayre syndrome
defect in Wilson Disease
mutation in ATP7B which codes for membrane-bound copper-binding ATPase
reduction of excretion of copper in bile
most reliable diagnostic finding in Wilson Disease
high copper content in biopsy of liver tissue
