Chap 37 - Inborn Error of Metabolism Flashcards
1
Q
- Motor inactivity and hypotonia
- Dysmorphic alterations of skull and face
- Stippled irregular calcification of patellae and greater trochanters
- Lack of liver peroxisomes
A
Zellweger disease (PEX1 mutation)
2
Q
Genetic aberration determined by single mutation that follow a mendelian pattern of inheritance
A
Monogenic disorders
3
Q
T/F. Mutation of DNA in germ cells will allow normal somatic phenotype of the individual but will affect descendants
A
TRUE. Inversely true too for mutation in somatic cells
4
Q
Individuals containing both normal and mutated cells, causing variable phenotypic expression from mild to severe.
A
Mosaic pattern
5
Q
Same mutation but have several different phenotypic expression
A
Polymorphic effect
6
Q
A measure of proportion of individuals w/ a given genotype who will show the phenotype and expressivity
A
Penetrance
7
Q
T/F. Autosomal dominant have a general tendency to manifest soon after birth.
A
FALSE. AD manifest late or long after birth
8
Q
T/F. Autosomal recessive have general tendency to manifest soon after birth. The defect is usually a BASIC PROTEIN.
A
FALSE. In terms of defect, mostly ENZYMES.
9
Q
Mutant gene affecting mainly one sex, and defect is mostly a BASIC PROTEIN.
A
X-linked
10
Q
Phenomenon during embryonic devt where female may suffer the same fate as males if one X chromosome is inactivated.
A
Lyon phenomenon
11
Q
Essential feature of mitochondrial gene and mutation is that inheritance is exclusive through:
A
Maternal lineage
12
Q
Genetic error in mitochondrial disease is most often due to a ________ that leads to alteration of a single amino acid
A
Single-point mutation
13
Q
Of the five complexes of the respiratory chain, the most often disordered complex is:
A
Complex-IV (cytochrome-c oxidase)
14
Q
Two common features in many of mitochondrial disorders
A
- Systemic lactic acidosis
- Red ragged fibers (clumping of mitochondria in muscle fibers)
15
Q
5 clinical points that may consider possibility of hereditary metabolic disease
A
- Similar illness w/ sibling or close relative
- Recurrent nonconvulsive episodes or intractable seizures
- Combination of unexplained neurologic symptoms (multiple neuronal systems)
- Progression of neurologic disease
- Developmental delay in px or relative
16
Q
T/F. Neonates nervous system function is essentially at a brainstem-spinal level
A
TRUE
17
Q
The first definite indication of disordered nervous system function among neonates is the occurrence of
A
Seizures
18
Q
Color reaction of ferric chloride w/ urine of PKU px
A
19
Q
Color reaction of ferric chloride w/ urine of MSUD px
A
NAVY BLUE
20
Q
Color reaction of ferric chloride w/ urine of Tyrosinemia px
A
Pale Green (Transient)
21
Q
Color reaction of ferric chloride w/ urine of Histidinemia px
A
Green brown
22
Q
Color reaction of ferric chloride w/ urine of Propionic acidemia px
A
PURPLE
23
Q
Color reaction of ferric chloride w/ urine of Methylmalonic aciduria px
A
24
Q
Metabolic defects w/ positive Benedict reaction
A
Galoctosemia, Fructose intolerance
(Test to know if with sugar in urine)
25
Metabolic defects w/ positive Nitroprusside reaction (red color)
Tyronsinemia
Homocystinuria
Cystenuria
(Test if w/ Thiol containing protein)
26
Metabolic defects w/ positive DNPH reaction
ALL w/ ferric chloride reaction
27
Autosomal recessive trait in neonates w/ early onset convulsions, jittery baby, failure to thrive. Due to increase excretion of xanthurenic acid in response to tryptophan load. Mutation is ALDH7A1 gene
Pyridoxine-dependent seizures
28
Increased conc of serum phenylalanine that is unresponsive to measures lowering it, due to lack of tetrahydrobiopterin, a cofactor of phenylalanine hydroxylase
Biopterin deficiency
29
Autosomal recessive defect in GALT, an enzyme catalyzing conversion of galactose-1-phosphate to uridine diphosphate galactose. Treatment is essentially dietary.
Galactosemia
30
Ketotic organic aciduria that can be prevented by marked protein reduction especially of leucine
Propionic academia
31
Organic aciduria causing a striking stale perspiration odor known as “sweaty foot syndrome”
Isovaleric academia
32
High levels of glycine but no aciduria, causing spongy degeneration.
Dietary protein & sodium benzoate & dextromethorphan is used
Nonketotic form of hyperglycinemia
33
Inherited hyperammonemia that is X-linked dominant, due to accumulation of ammonia or urea cycle intermediates
OTC deficiency (ornithine transcarbamylase)
34
Late-onset hyperammonemias, w/ brittle hair, excessive dryness.
Arignosuccinic aciduria
35
Late-onset hyperammonemias, w/ spastic diplegia
Arginase deficiency
36
MSUD has deficiency of the enzyme ______ resulting to accumulation of branched amino acids of \_\_\_\_, \_\_\_\_, and \_\_\_\_\_.
Alpha-keto acid dehydrogenase
* Leucine
* Isoleucine
* Valine
37
This accounts for the maple syrup odor of urine
Alpha-hydroxybutyric acid
38
Nonhereditary neonatal metabolic diseases, important to distinguish from hereditary ones
* Hypocalcemia
* Hypoglycemia
* Cretinism
* Idiopathic hypercalcemia
39
Important clues for diagnosis of neonatal metabolic diseases
* Neonatal disease or unexplained death of sibling or maternal relative
* Dislike of protein
40
Hallmark of all hereditary metabolic disease
Psychosensorimotor regression
41
Group of inherited metabolic disease characterized by progressive, symmetrical, massive destruction of white matter in brain & spinal cord
Leukodystrophy
42
Diseases displaying Cherry-red macular spot
* Tay-Sachs disease
* GM1 gangliosidosis
* Niemann-Pick disease Type A-D
* Farber lipogranulomatosis
* Metachromatic leukodystrophy
43
Tay-Sach’s disease
Enzyme deficiency:
Accumulated metabolite:
Mutation:
* Hexosaminidase A
* GM2 ganglioside
* HEXA mutation
44
Gaucher disease
Enzyme deficiency:
Accumulated metabolite:
Mutation:
* Glucocerebrosidase
* Glucosylceramide
* GBA mutation
45
Characteristic pathologic feature w/ wrinkled appearance of cytoplasm & eccentricity of nucleus biopsied from liver or spleen
Gaucher cells
46
Infantile Niemann-Pick Disease
Enzyme deficiency:
Accumulated metabolite:
Mutation:
* Sphingomyelinase
* Spingomyelin, cholesterol
* NPC mutation
47
Seen in the bone marrow of Niemann-Pick Disease, important laboratory findings
Foam cells (Vacuolated histiocytes)
48
The disease should be suspected in an infant having the facial features of mucopolysaccharidosis and severe early onset neurologic symptoms
Generalized GM1 Gangliosidosis
49
Krabbe Disease
Enzyme deficiency:
Accumulated metabolite:
Mutation:
* Galactocerebrosidase
* Galatosylceramide
* GALC mutation
* Globoid cell leukodystrophy
50
Farber Disease
Enzyme deficiency:
Accumulated metabolite:
Mutation:
Characteristic is periarticular, subcutaneous swelling and progressive arthropathy leading to ankylosis
* Ceramidase
* Ceramide
* ASAH1 gene
51
Leukodystrophies in which NYSTAGMUS is an invariable finding
* Pelizaeus-Merzbacher disease (PLP1 mutation)
* Cockayne syndrome
52
Leukodystrophy w/ behavioral regression, enlarging head, spongy degeneration of brain in MRI, elevated urinary NAA
Canavan disease
53
Progressive macrocephaly, failure to thrive, psychomotor retardation, seizures, craniospinal spasticity w/ Rosenthal fibers in astrocytes
Alexander disease (GFAP Mutation)
54
Progressive cerebral poliodystrophy, becoming a “walnut brain” similar to CJD
Alpers disease (POLG mutation)
55
Psychomotor regression, episodic hyperventilation, hypotnia, convulsions w/ periods of normalcy
Congenital Lactic acidosis
56
* Oculomotor abnormalities
* Psychomotor regression & corticospinal
* Renal tubular acidosis
* Defect in inositol polyphosphate phosphatase of Golgi complex
Oculocerebrorenal (Lowe) Syndrome
57
* Sex-linked
* Steel wool hair
* Metaphysial spurring
* Tortuous cerebral and systemic arteries
* Low copper levels, opposite of Wilsons due to defect in copper transport (ATP7A mutation)
* Failure of absorption of copper from gut to tissue
Menkes Disease (Trichopoliodystrophy)
58
Diffrentiation of inherited metabolic disorders in infants depend on the ff:
* Charaterisrtic neurologic and ophtalmic signs
* Visceromegaly
* Special dysmorphic feature
* Results of relatively simple lab results
59
Inherited metabolic disorder w/ visceromegaly
Niemann-Pick
Infantile Gaucher
Pompe
Farber
Sandhoff
Mucolipidosis
60
Clinical manifestation of poliodystrophy
Early onset seizures
Myoclonus
Blindness w/ retinal changes
Mental regression
61
Clinical manifestation of leukodystrophy
Early onset spastic paralysis
Ataxia
Visual impairment w/ optic atrophy
\*Seizures & intellectual detoriation occurs LATE
62
PKU
Enzyme deficiency:
Accumulated metabolite:
Characteristic hyperactivity, self injurious behavior, repititious digital mannerism
Treatment:
Phenylalanine hydroxylase
Phenylalanine & phenylpyruvic acid
Phenylalanine restriciton maintained at 5-10mg/dL level
63
Predominantly dermatologic aminoacidopathy w/ psychomotor regression, prominent language defect and ocular involvement (cataract etc)
Hereditary Tyronisinemia
64
Resembles pellagra
Result of transport error of neutral amino acids across renal tubules
Treat w/ Nicotinamide
Hartnup Disease (SLC6A19 Mutation)
65
Lysosomal storage disease due to defect in Arylsulfatase A enzyme preventing conversion of sulfatide to cerebroside resulting to widespread degeneration of myelinated fibers in the CNS & PNS
Metachromatic Leukodystrophy
66
Group of disease in which storage of lipid in neurons combined w/ polysaccharides in connective tissues resulting to neurologic and skeletal abnormalities.
Accumulation of glycosaminoglycans
Resulting to obliteration of subarachnoid space, obstructive HCP or compression of cervical cord
Mucopolysaccharidoses
67
The only X-linked Mucopolysaccharidoses
MPS II (Hunter Syndrome)
68
MPS w/ enzyme deficiency of alpha-L-Iduronidase
Accumulation of dermatan sulfate & heparan sulfate
MPS I (Hurler Syndrome)
69
Only X-linked MPS, w/ IDURONATE SULFATASE DEFICIENCY
MPS II (Hunter)
70
Continuous myoclonus w/ opsoclonic movt of eyes, treatment w/ dexamethasone
Infantile Opsoclonus-Myoclonus Syndrome
71
Mutation in Wilsons disease
ATP7B (membrane-bound, copper binding ATPase)
72
Two fundamental disturbances in copper metabolism in Wilsons Disease
1) reduced rate of incoporation of copper to ceruloplasmin
2) reduced biliary excretion of copper
73
Clinical manifestaiton of Wilsons
Extrapyramidal symptoms
Cirrhosis
Hemolytic anemia
renal tubular changes
Kayser-Fleischer rings
74
Usual onset of Wilsons
Initial event occuring in Wilsons
2nd-3rd decade of life
Deposition of copper in liver
75
Notable feature of Wilsons
Tendency for motor disorders be concentrated in Oropharyngeal musculature then spread caudally
76
T/F. Kayser-Fleischer ring always evident at hepatic stage of the disease
FALSE. Only in 25 % of cases BUT once w/ neurologic symptoms are present likely ALWAYS present
77
Laboratory findings in Wilsons disease
Low ceruloplasmin (\<20mg/dL)
Low serum copper (\<11 mM/L)
Inc urinary copper excretion (\>100mg Cu/24h)
78
Most reliable diagnostic findings in Wilsons disease
High copper content in biopsy of liver tissue
79
Treatment of Wilsons disease
1) Reduced dietary copper (liver, mushrooms, cocoa, nuts, shellfish)
2) Chelation w/ D-penicillamine w/ pyridoxine
3) Zinc sulfate to reduce intestinal absorption of copper
80
Definite curative treatment for Wilsons
Liver transplant
81
Pigmentary degeneration of the globus pallidus due to PANK mutation resulting to iron deposits in the said area
Hallervorden-Spatz Disease
82
Charateristic MRI finding appearing as a intense rim of black in the putamen w/ small white are in the medial part representing necrosis in PANK mutation
Eye of the Tiger sign
83
Charateristic MRI finding in Wilsons disease
Giant Panda Face Sign
84
X-linked hereditary choreoathetosis w/ self-mutilation and hyperuricemia
Lesch-Nyhan Syndrome (HPRT1 gene)
85
Idiopathic calcification of BG & cerebellum resulting to choreoathetosis & rigidity but NORMAL calcium levels
Fahr Disease
86
Tetany, seizures and choreoathetosis w/ calcification of BG as a result of low serum calcium
Hypoparathyroidism / Pseudohypoparathyroidism
87
X-linked recessive trait w/ fundamental impairment in perixisomal membrane transport (ABCD1 mutation).
Associated w/ Addisons disease (bronzing & hyperpigmentation of skin, low serum cortisol, elev K, low Na, low Ca)
Adrenoleukodystrophy (Sudanophilic)
88
Main differential diagnosis for adrenoleukodystrophy
Multiple sclerosis
89
VLCFAs measured for Adrenoleukodystrophy
hexacosanoic acid
docosahexacosanoic acid
tetracosanoic acid
90
Refers to a heterogenous group of disroders in which NO enzyme defect or special staining characteristic of degenerated white matter identified
Orthochromatic Leukodystrophies
91
Autosomal recessive presenting w/ cataracts, xanthomas tendon sheaths and lungs, psychomotor regression.
Basic defect: synthesis of primary bile acids leading to inc hepatic production of cholesterol & cholestanol.
Long-term tx chenodeoxycholic acid
Cerebrotendinous Xanthomatosis (CYP27A Mutation)
92
THREE metabolic disorders to ALWAYS consider if presenting as STROKE
1) Homocystinuria
2) Fabry disease
3) Sulfite oxidase deficiency
93
Autosomal recessive that simulates Marfan disease (w/ skeletal abnormalities), but w/ mental retardation, and stroke
Homocystinuria
94
Most common dermal manifestation of Homocystinuria
Livedo reticularis
95
Pathologic findings of Homocystinuria that could explain cerebrovascular lesions
* Blood vessels thicken & fibrosis
* Abnormality of platelet favoring clot formation and thrombosis
96
Enzyme deficiency related to Homocystinuria
Cysthionine synthase
5-10 methylenetetrahydrofolate reductase
97
X-linked trait known as angiokeratoma corporis diffusum
Manifest as intermittent lancinating pain & dysesthesias of extremities, & thrombotic events
Fabry Disease
98
Primary enzyme deficit & metabolite accumulation in Fabry disease
alpha-galactosidase A
Ceramide trihexoside
99
Useful principle in recognizing metabolic brain disease in adolescents
Regression of cognitive & intellectual function w/ or w/o personality & behavioral changes
100
Subsarcolemmal and intermyofibrillar collections of membranous material in Type 1 muscle fibers as visualized by Gomori trichrome stain in frozen section
Red Ragged Fiber
101
Syndrome of epilepsy, deafness, devt delay w/ red ragged fibers
MERRF Syndrome
102
Mitochondrial disorders that may have NO red ragged fibers & lactic acidosis
Progressive external ophthalomoplegia (PEO)
Kearns-Sayre variant
Leber optic neuropathy
103
Mitochondrial disorders that may have NO red ragged fibers BUT WITH lactic acidosis
Leigh Syndrome
NARP
104
Mitochondrial disorders that HAVE red ragged fibers BUT NO lactic acidosis
Red ragged fiber polymyopathy
Myoneural-GI encephalopathy
105
Mitochondrial disorders that HAVE BOTH red ragged fibers & lactic acidosis
MERRF
MELAS
106
Histologic feature that unites mitochondrial myopathies is the presence of
Red Ragged Fibers
107
Mitochondrial disease that has combination of progressive ptosis and symmetrical ophthalmoplegia
PEO
108
Syndrome of retinitis pigmentosa, ataxia, heart block and conduction defects, elevated CSF protein w/ PEO
May have sensorineural deafness, seizures, pyramidal signs
Kearns-Sayre Syndrome
109
Mitochondrial disease w/ Onset of neurologic difficulty during first year of life presenting as poor head control, hypotonia, anorexia, seizures, sometimes precipitated by infection or surgical operation.
Leigh disease
110
Pathologic changes are symmetrical foci of spongy necrosis w/ myelin degeneration, vascular proliferation, & gliosis of thalami mibrain pons; resembling Wernickes disease
Leigh Disease
111
NARP means:
w/ defective what
Neuropathy, Ataxia, Retinitis Pigmentosa Syndrome
Defect in ATPase-6 of complex V
112
Myoclonic epilepsy or ataxia w/ myopathy
MERRF
113
Normal early devt followed by poor growth, seizures, recurrent acute ep of stroke
MELAS
114
Charateristic feature of MELAS
Prolonged focal seizures, w/c heralds a stroke and produce an unusual radiographic pattern of infarction.
115
T/F. The normal findings of lab test including muscle biopsy rules out mitchondrial disorder
FALSE. Diagnosis is clinical syndrome, family hx, corroborating evidence
116
Characteristic neurologic findings of mitochondrial disease
MERFF: ataxia, seizures, myoclonus
MELAS: migraine-like HA, small strokes w/ preceding seizures
PEO: symmetrical ptosis and ophthalmoplegia
Kearns-Sayre Syndrome: PEO w/ retinitis pigmentosa, conduction blocks, neuropathy, deafnes
Leber type: Optic atrophy
Myopathy: proximal weakness
