Inherited Metabolic Diseases Flashcards by kat remigio

number of mitochondrial genes

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homoplasmy

the presence of either completely normal or completely mutant mitochondrial DNA

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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

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The first definite indication of disordered nervous system function is likely to be the occurrence of

seizures

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three most frequently identified hereditary metabolic diseases that do not become clinically manifest in the neonatal period

phenylketonuria
hyperphenylalaninemia
congenital hypothyroidism

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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

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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

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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

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Beta Galactosidase deficiency

GM1 gangliosidosis

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N-acetylhexosaminidase alpha subunit deficiency

Tay Sachs Disease

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N-acetylhexosaminidase beta subunit deficiency

Sandhoff disease

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GM2 activator deficiency

Acitivator Deficiency

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arylsulfatase (sulfatidase), sulfatide activator (saposin B) deficiency

Metachromatic Leukodystrophy

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galactocerebrosidase deficiency

Krabbe

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Alpha galactosidase A deficiency

Fabry disease

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Glucocerebrosidase deficiency

Gaucher disease

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sphingomyelinase deficiency

Type A and B Niemann Pick Disease

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Ceramidase deficiency

Farber Disease

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Alpha Galactosidase B deficiency

Schindler Disease

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deficiency of alpha keto acid dehydrogenase
resulting in accumulation of branched-chain amino acids leucine, isoleucine, valine
autosomal recessive

Maple Syrup Urine Disease

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urine test for MSUD

2,4 dinitrophenylhydrazine DNPH

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seizures, tremulousness, drowsiness occur with blood sugar levels less than
mature infant:
premature:

mature less than 30mg/dL

premature 20mg/dL

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hallmark of all the hereditary metabolic diseases

psychosensorimotor regression

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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

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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

1. reduction of dietary copper to 1mg/d avoidance of copper rich foods: liver, mushrooms, cocoa, chocolate, nuts, shellfish 2. 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