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Adams 10th Ed > Chap 37 - Inborn Error of Metabolism > Flashcards

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)

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2
Q

Genetic aberration determined by single mutation that follow a mendelian pattern of inheritance

A

Monogenic disorders

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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

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4
Q

Individuals containing both normal and mutated cells, causing variable phenotypic expression from mild to severe.

A

Mosaic pattern

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5
Q

Same mutation but have several different phenotypic expression

A

Polymorphic effect

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6
Q

A measure of proportion of individuals w/ a given genotype who will show the phenotype and expressivity

A

Penetrance

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7
Q

T/F. Autosomal dominant have a general tendency to manifest soon after birth.

A

FALSE. AD manifest late or long after birth

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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.

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9
Q

Mutant gene affecting mainly one sex, and defect is mostly a BASIC PROTEIN.

A

X-linked

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10
Q

Phenomenon during embryonic devt where female may suffer the same fate as males if one X chromosome is inactivated.

A

Lyon phenomenon

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11
Q

Essential feature of mitochondrial gene and mutation is that inheritance is exclusive through:

A

Maternal lineage

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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

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13
Q

Of the five complexes of the respiratory chain, the most often disordered complex is:

A

Complex-IV (cytochrome-c oxidase)

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14
Q

Two common features in many of mitochondrial disorders

A
  • Systemic lactic acidosis
  • Red ragged fibers (clumping of mitochondria in muscle fibers)
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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
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16
Q

T/F. Neonates nervous system function is essentially at a brainstem-spinal level

A

TRUE

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17
Q

The first definite indication of disordered nervous system function among neonates is the occurrence of

A

Seizures

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18
Q

Color reaction of ferric chloride w/ urine of PKU px

A
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19
Q

Color reaction of ferric chloride w/ urine of MSUD px

A

NAVY BLUE

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20
Q

Color reaction of ferric chloride w/ urine of Tyrosinemia px

A

Pale Green (Transient)

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21
Q

Color reaction of ferric chloride w/ urine of Histidinemia px

A

Green brown

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22
Q

Color reaction of ferric chloride w/ urine of Propionic acidemia px

A

PURPLE

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23
Q

Color reaction of ferric chloride w/ urine of Methylmalonic aciduria px

A
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24
Q

Metabolic defects w/ positive Benedict reaction

A

Galoctosemia, Fructose intolerance

(Test to know if with sugar in urine)

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25
Q

Metabolic defects w/ positive Nitroprusside reaction (red color)

A

Tyronsinemia

Homocystinuria

Cystenuria

(Test if w/ Thiol containing protein)

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26
Q

Metabolic defects w/ positive DNPH reaction

A

ALL w/ ferric chloride reaction

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27
Q

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

A

Pyridoxine-dependent seizures

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28
Q

Increased conc of serum phenylalanine that is unresponsive to measures lowering it, due to lack of tetrahydrobiopterin, a cofactor of phenylalanine hydroxylase

A

Biopterin deficiency

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29
Q

Autosomal recessive defect in GALT, an enzyme catalyzing conversion of galactose-1-phosphate to uridine diphosphate galactose. Treatment is essentially dietary.

A

Galactosemia

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30
Q

Ketotic organic aciduria that can be prevented by marked protein reduction especially of leucine

A

Propionic academia

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31
Q

Organic aciduria causing a striking stale perspiration odor known as “sweaty foot syndrome”

A

Isovaleric academia

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32
Q

High levels of glycine but no aciduria, causing spongy degeneration.

Dietary protein & sodium benzoate & dextromethorphan is used

A

Nonketotic form of hyperglycinemia

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33
Q

Inherited hyperammonemia that is X-linked dominant, due to accumulation of ammonia or urea cycle intermediates

A

OTC deficiency (ornithine transcarbamylase)

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34
Q

Late-onset hyperammonemias, w/ brittle hair, excessive dryness.

A

Arignosuccinic aciduria

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35
Q

Late-onset hyperammonemias, w/ spastic diplegia

A

Arginase deficiency

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36
Q

MSUD has deficiency of the enzyme ______ resulting to accumulation of branched amino acids of ____, ____, and _____.

A

Alpha-keto acid dehydrogenase

  • Leucine
  • Isoleucine
  • Valine
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37
Q

This accounts for the maple syrup odor of urine

A

Alpha-hydroxybutyric acid

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38
Q

Nonhereditary neonatal metabolic diseases, important to distinguish from hereditary ones

A
  • Hypocalcemia
  • Hypoglycemia
  • Cretinism
  • Idiopathic hypercalcemia
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39
Q

Important clues for diagnosis of neonatal metabolic diseases

A
  • Neonatal disease or unexplained death of sibling or maternal relative
  • Dislike of protein
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40
Q

Hallmark of all hereditary metabolic disease

A

Psychosensorimotor regression

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41
Q

Group of inherited metabolic disease characterized by progressive, symmetrical, massive destruction of white matter in brain & spinal cord

A

Leukodystrophy

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42
Q

Diseases displaying Cherry-red macular spot

A
  • Tay-Sachs disease
  • GM1 gangliosidosis
  • Niemann-Pick disease Type A-D
  • Farber lipogranulomatosis
  • Metachromatic leukodystrophy
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43
Q

Tay-Sach’s disease

Enzyme deficiency:

Accumulated metabolite:

Mutation:

A
  • Hexosaminidase A
  • GM2 ganglioside
  • HEXA mutation
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44
Q

Gaucher disease

Enzyme deficiency:

Accumulated metabolite:

Mutation:

A
  • Glucocerebrosidase
  • Glucosylceramide
  • GBA mutation
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45
Q

Characteristic pathologic feature w/ wrinkled appearance of cytoplasm & eccentricity of nucleus biopsied from liver or spleen

A

Gaucher cells

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46
Q

Infantile Niemann-Pick Disease

Enzyme deficiency:

Accumulated metabolite:

Mutation:

A
  • Sphingomyelinase
  • Spingomyelin, cholesterol
  • NPC mutation
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47
Q

Seen in the bone marrow of Niemann-Pick Disease, important laboratory findings

A

Foam cells (Vacuolated histiocytes)

48
Q

The disease should be suspected in an infant having the facial features of mucopolysaccharidosis and severe early onset neurologic symptoms

A

Generalized GM1 Gangliosidosis

49
Q

Krabbe Disease

Enzyme deficiency:

Accumulated metabolite:

Mutation:

A
  • Galactocerebrosidase
  • Galatosylceramide
  • GALC mutation
  • Globoid cell leukodystrophy
50
Q

Farber Disease

Enzyme deficiency:

Accumulated metabolite:

Mutation:

Characteristic is periarticular, subcutaneous swelling and progressive arthropathy leading to ankylosis

A
  • Ceramidase
  • Ceramide
  • ASAH1 gene
51
Q

Leukodystrophies in which NYSTAGMUS is an invariable finding

A
  • Pelizaeus-Merzbacher disease (PLP1 mutation)
  • Cockayne syndrome
52
Q

Leukodystrophy w/ behavioral regression, enlarging head, spongy degeneration of brain in MRI, elevated urinary NAA

A

Canavan disease

53
Q

Progressive macrocephaly, failure to thrive, psychomotor retardation, seizures, craniospinal spasticity w/ Rosenthal fibers in astrocytes

A

Alexander disease (GFAP Mutation)

54
Q

Progressive cerebral poliodystrophy, becoming a “walnut brain” similar to CJD

A

Alpers disease (POLG mutation)

55
Q

Psychomotor regression, episodic hyperventilation, hypotnia, convulsions w/ periods of normalcy

A

Congenital Lactic acidosis

56
Q
  • Oculomotor abnormalities
  • Psychomotor regression & corticospinal
  • Renal tubular acidosis
  • Defect in inositol polyphosphate phosphatase of Golgi complex
A

Oculocerebrorenal (Lowe) Syndrome

57
Q
  • 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
A

Menkes Disease (Trichopoliodystrophy)

58
Q

Diffrentiation of inherited metabolic disorders in infants depend on the ff:

A
  • Charaterisrtic neurologic and ophtalmic signs
  • Visceromegaly
  • Special dysmorphic feature
  • Results of relatively simple lab results
59
Q

Inherited metabolic disorder w/ visceromegaly

A

Niemann-Pick

Infantile Gaucher

Pompe

Farber

Sandhoff

Mucolipidosis

60
Q

Clinical manifestation of poliodystrophy

A

Early onset seizures

Myoclonus

Blindness w/ retinal changes

Mental regression

61
Q

Clinical manifestation of leukodystrophy

A

Early onset spastic paralysis

Ataxia

Visual impairment w/ optic atrophy

*Seizures & intellectual detoriation occurs LATE

62
Q

PKU

Enzyme deficiency:

Accumulated metabolite:

Characteristic hyperactivity, self injurious behavior, repititious digital mannerism

Treatment:

A

Phenylalanine hydroxylase

Phenylalanine & phenylpyruvic acid

Phenylalanine restriciton maintained at 5-10mg/dL level

63
Q

Predominantly dermatologic aminoacidopathy w/ psychomotor regression, prominent language defect and ocular involvement (cataract etc)

A

Hereditary Tyronisinemia

64
Q

Resembles pellagra

Result of transport error of neutral amino acids across renal tubules

Treat w/ Nicotinamide

A

Hartnup Disease (SLC6A19 Mutation)

65
Q

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

A

Metachromatic Leukodystrophy

66
Q

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

A

Mucopolysaccharidoses

67
Q

The only X-linked Mucopolysaccharidoses

A

MPS II (Hunter Syndrome)

68
Q

MPS w/ enzyme deficiency of alpha-L-Iduronidase

Accumulation of dermatan sulfate & heparan sulfate

A

MPS I (Hurler Syndrome)

69
Q

Only X-linked MPS, w/ IDURONATE SULFATASE DEFICIENCY

A

MPS II (Hunter)

70
Q

Continuous myoclonus w/ opsoclonic movt of eyes, treatment w/ dexamethasone

A

Infantile Opsoclonus-Myoclonus Syndrome

71
Q

Mutation in Wilsons disease

A

ATP7B (membrane-bound, copper binding ATPase)

72
Q

Two fundamental disturbances in copper metabolism in Wilsons Disease

A

1) reduced rate of incoporation of copper to ceruloplasmin
2) reduced biliary excretion of copper

73
Q

Clinical manifestaiton of Wilsons

A

Extrapyramidal symptoms

Cirrhosis

Hemolytic anemia

renal tubular changes

Kayser-Fleischer rings

74
Q

Usual onset of Wilsons

Initial event occuring in Wilsons

A

2nd-3rd decade of life

Deposition of copper in liver

75
Q

Notable feature of Wilsons

A

Tendency for motor disorders be concentrated in Oropharyngeal musculature then spread caudally

76
Q

T/F. Kayser-Fleischer ring always evident at hepatic stage of the disease

A

FALSE. Only in 25 % of cases BUT once w/ neurologic symptoms are present likely ALWAYS present

77
Q

Laboratory findings in Wilsons disease

A

Low ceruloplasmin (<20mg/dL)

Low serum copper (<11 mM/L)

Inc urinary copper excretion (>100mg Cu/24h)

78
Q

Most reliable diagnostic findings in Wilsons disease

A

High copper content in biopsy of liver tissue

79
Q

Treatment of Wilsons disease

A

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
Q

Definite curative treatment for Wilsons

A

Liver transplant

81
Q

Pigmentary degeneration of the globus pallidus due to PANK mutation resulting to iron deposits in the said area

A

Hallervorden-Spatz Disease

82
Q

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

A

Eye of the Tiger sign

83
Q

Charateristic MRI finding in Wilsons disease

A

Giant Panda Face Sign

84
Q

X-linked hereditary choreoathetosis w/ self-mutilation and hyperuricemia

A

Lesch-Nyhan Syndrome (HPRT1 gene)

85
Q

Idiopathic calcification of BG & cerebellum resulting to choreoathetosis & rigidity but NORMAL calcium levels

A

Fahr Disease

86
Q

Tetany, seizures and choreoathetosis w/ calcification of BG as a result of low serum calcium

A

Hypoparathyroidism / Pseudohypoparathyroidism

87
Q

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)

A

Adrenoleukodystrophy (Sudanophilic)

88
Q

Main differential diagnosis for adrenoleukodystrophy

A

Multiple sclerosis

89
Q

VLCFAs measured for Adrenoleukodystrophy

A

hexacosanoic acid

docosahexacosanoic acid

tetracosanoic acid

90
Q

Refers to a heterogenous group of disroders in which NO enzyme defect or special staining characteristic of degenerated white matter identified

A

Orthochromatic Leukodystrophies

91
Q

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

A

Cerebrotendinous Xanthomatosis (CYP27A Mutation)

92
Q

THREE metabolic disorders to ALWAYS consider if presenting as STROKE

A

1) Homocystinuria
2) Fabry disease
3) Sulfite oxidase deficiency

93
Q

Autosomal recessive that simulates Marfan disease (w/ skeletal abnormalities), but w/ mental retardation, and stroke

A

Homocystinuria

94
Q

Most common dermal manifestation of Homocystinuria

A

Livedo reticularis

95
Q

Pathologic findings of Homocystinuria that could explain cerebrovascular lesions

A
  • Blood vessels thicken & fibrosis
  • Abnormality of platelet favoring clot formation and thrombosis
96
Q

Enzyme deficiency related to Homocystinuria

A

Cysthionine synthase

5-10 methylenetetrahydrofolate reductase

97
Q

X-linked trait known as angiokeratoma corporis diffusum

Manifest as intermittent lancinating pain & dysesthesias of extremities, & thrombotic events

A

Fabry Disease

98
Q

Primary enzyme deficit & metabolite accumulation in Fabry disease

A

alpha-galactosidase A

Ceramide trihexoside

99
Q

Useful principle in recognizing metabolic brain disease in adolescents

A

Regression of cognitive & intellectual function w/ or w/o personality & behavioral changes

100
Q

Subsarcolemmal and intermyofibrillar collections of membranous material in Type 1 muscle fibers as visualized by Gomori trichrome stain in frozen section

A

Red Ragged Fiber

101
Q

Syndrome of epilepsy, deafness, devt delay w/ red ragged fibers

A

MERRF Syndrome

102
Q

Mitochondrial disorders that may have NO red ragged fibers & lactic acidosis

A

Progressive external ophthalomoplegia (PEO)

Kearns-Sayre variant

Leber optic neuropathy

103
Q

Mitochondrial disorders that may have NO red ragged fibers BUT WITH lactic acidosis

A

Leigh Syndrome

NARP

104
Q

Mitochondrial disorders that HAVE red ragged fibers BUT NO lactic acidosis

A

Red ragged fiber polymyopathy

Myoneural-GI encephalopathy

105
Q

Mitochondrial disorders that HAVE BOTH red ragged fibers & lactic acidosis

A

MERRF

MELAS

106
Q

Histologic feature that unites mitochondrial myopathies is the presence of

A

Red Ragged Fibers

107
Q

Mitochondrial disease that has combination of progressive ptosis and symmetrical ophthalmoplegia

A

PEO

108
Q

Syndrome of retinitis pigmentosa, ataxia, heart block and conduction defects, elevated CSF protein w/ PEO

May have sensorineural deafness, seizures, pyramidal signs

A

Kearns-Sayre Syndrome

109
Q

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.

A

Leigh disease

110
Q

Pathologic changes are symmetrical foci of spongy necrosis w/ myelin degeneration, vascular proliferation, & gliosis of thalami mibrain pons; resembling Wernickes disease

A

Leigh Disease

111
Q

NARP means:

w/ defective what

A

Neuropathy, Ataxia, Retinitis Pigmentosa Syndrome

Defect in ATPase-6 of complex V

112
Q

Myoclonic epilepsy or ataxia w/ myopathy

A

MERRF

113
Q

Normal early devt followed by poor growth, seizures, recurrent acute ep of stroke

A

MELAS

114
Q

Charateristic feature of MELAS

A

Prolonged focal seizures, w/c heralds a stroke and produce an unusual radiographic pattern of infarction.

115
Q

T/F. The normal findings of lab test including muscle biopsy rules out mitchondrial disorder

A

FALSE. Diagnosis is clinical syndrome, family hx, corroborating evidence

116
Q

Characteristic neurologic findings of mitochondrial disease

A

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

Adams 10th Ed (8 decks)

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