INHERITED METABOLIC DISEASES Flashcards
These mutations can be of a single base pair (point mutation),
an insertion or deletion of nucleotides, or structural
rearrangements of a sequence of DNA, such as translocations
or inversions; because the most important of these
involve the coding (exonic) portion of DNA, they are
likely to disrupt the structure and function of enzymes or
cellular structural proteins
monogenic d/o characterized by single mutation that follow mendelian inheritance
sequence of a gene and are by convention present with
a frequency of greater than 1 percent in the population;
these play a role in the genesis of disease but do not
obligatorily result in a somatic aberration or alternatively,
they interact with exogenous environmental factors
SNP which are variations of the wild type
3 types of Mendelian inheritance
AD, AR, Sex-linked
An
individual, with both normal cells and cells containing the
mutant gene, is referred to as a _______
mosaic.
a measure of
the proportion of individuals with a given genotype who
will show the phenotype, and expressivity, referring to
the severity of disease in an affected individual.
penetrance
In X-linked disorders, the mutant
gene affects mainly one sex, the female will suffer the same fate as the male if one X chromosome has been inactivated,
as happens in most cells during embryonic development
because of this phenomenon
Lyon phenomenon
__________ (“the other human genome”) is a double-stranded, circular molecule that encodes the protein subunits required mainly for translation of the proteins located on the mitochondrial inner membrane.
Mitochondrial DNA
How many of the mitochondrial genes partake in cellular process of oxidative phosphorylation?
13/37
The essential feature of mitochondrial genes and the
mutations to which they are subject is that they are inherited
almost exclusively through _______
maternal lineage.
mitochondria with mutant genes
may exist next to normal mitochondria , a
state that permits an otherwise lethal mutation to persist
heteroplasmy
mechanism of mitochondrial DNA replication
there are contributions during cell division
from the genes of various mitochondria to the progeny of
dividing cells
Of the five complexes that make up the respiratory chain,
_____________ is the one most often
disordered, and its deficient function gives rise to lactic
acidosis, a feature common to many of the mitochondrial
disorders
cytochrome-c oxidase (complex IV)
Two characteristics
traceable to mitochondrial abnormalities are
1.
2.
- ragged red fibers, a clumping of mitochondria in muscle fibers described in more detail further on, and the
- systemic lactic acidosis.
Diagnosis of hereditary metabolic diseases:
- A neurologic disorder of similar type in a sibling or
close relative - Recurrent ________
or intractable seizures in infants or young
children or infantile spasms and progressive myoclonic
seizures in the absence of neonatal hypoxiaischemia - Some combination of unexplained __________
- Progression of a neurologic disease measured in
months, or a few years - Developmental delay in an individual if there are no
congenital somatic abnormalities or developmental
delay in a sibling or close relative
nonconvulsive episodes of impaired consciousness
symmetrical or generalized spastic weakness, cerebellar ataxia, extrapyramidal disorder, deafness, or blindness
Initial assessment in neonates to assess cerebral function
1 . Control of ________ and _________; regulation
of thirst, fluid balance, and appetite-hypothalamus-
brainstem mechanisms
2. Certain elemental _________ such as sucking,
rooting, swallowing, grasping-brainstem-cerebellar
mechanisms
3. Movements and postures of the neck, trunk, and
limbs, such as reactions of support, extension of the
neck and trunk, flexion movements, and steppagel
4.________of limbs and trunk-spinal neuronal and
neuromuscular function
respiration and body temperature
automatisms,
Muscle tone
5.______________-tegmental midbrain and
pontine mechanisms (a modified optokinetic nystagmus
can be recognized by the third day of life)
6. The state of _________________and capacity of the examiner to make contact) as well as sleep-waking and electroencephalographic
patterns-mesencephalic-diencephalic mechanisms
7. Certain reflexive reactions such as the______________________ with possible
cortical facilitation
Reflex eye movements
alertness and attention (stimulus responsivity
startle (Moro)
response and placing reactions of the foot and handupper
brainstem-spinal mechanisms
Initial clues to metabolic disease
difficulties in feeding
Other classification of metabolic dse
if clinical examination consistently
discloses any one of the 3 syndromes, the chances are 2 in 3 that by the_________ year the child will be manifestly abnormal neurologically.
(1) hyperkinetic-hypertonic,
(2) apathetic-hypotonic, or
(3) unilateral or hemisyndromic.
seventh
It is important to note that the three most frequently
identified hereditary metabolic diseases-_________________ do not manifest in the neonatal period
phenylketonuria
(PKU), hyperphenylalaninemia, and congenital hypothyroidism
Sx of Pyridoxine dependent Sz
characterized by the early onset of convulsions, sometimes occurring in utero; failure to thrive; hypertonia-hyperkinesia; irritability;
tremulous movements ("jittery baby"); exaggerated
auditory startle (hyperacusis); and later, if untreated, by
psychomotor retardationPyridoxine dependent Sz
The specific laboratory abnormality
is an increased excretion of _________ in response
to a tryptophan load.
There are decreased levels of_________and _____________ in brain tissue.
The mutation is of the _________gene.
xanthurenic acid
pyridoxal- 5-phosphate
gamma-aminobutyric acid (GABA)
ALDH7 Al
Pyridoxine dependent Sz
There was a decreased amount of ___________ in the cerebral hemispheres and a depletion of neurons in the ___________, with gliosis
central white matter
thalamic nuclei and cerebellum
Pyridoxine dependent Sz
in pyridoxine deficiency, the administration of ________ suppresses the seizure state, and daily
doses of ______ permit normal development.
50 to 100 mg of vitamin B6
40 mg
Some patients with increased concentrations of serum
phenylalanine in the neonatal period are unresponsive
to measures that lower phenylalanine. They are usually
found to have a defect in__________
biopterin metabolism.
B i o pte ri n Defi c i e ncy
Within a few months, developmental
delay becomes prominent. Unlike in PKU, phenylalanine
hydroxylase enzyme levels are normal, but there
is a lack of _________ which is a cofactor of
phenylalanine hydroxylase
tetrahydrobiopterin,
B i o pte ri n Defi c i e ncy
Treatment consists of administration
of tetrahydrobiopterin in a dosage of ___________in combination with a low-phenylalanine diet.
7.5 mg/ kg/ d
G a l a ctose m i a
Inheritance of this disorder is ___________.
The biochemical abnormality consists of a defect in _________________ the enzyme that
catalyzes the conversion of galactose-1-phosphate to uridine diphosphate galactose
autosomal recessive
galactose- 1-phosphate uridyl transferase (GALT),
Initial Sx of severe galactossemia:
In the typical (severe) form, the onset of symptoms is in the first days of life, after the ingestion of milk; vomiting and diarrhea are followed by a failure to thrive
galactossemia:
In a small number, there is thrombocytopenia
with cerebral bleeding. Cataracts form as a result
of the accumulation of ________ in the lens.
galactitol
Surviving pts with galactossemia:
surviving infants have shown delayed psychomotor development (IQ about 85), visual impairment, osteoporosis, ovarian failure, and residual cirrhosis, sometimes with splenomegaly and ascites
Dx of galactossemia
Pathology: ___________ of the white matter and some loss of _____________ in the cerebellum, and also gliosis
The diagnostic laboratory findings are an elevated blood galactose level, low glucose, galactosuria, and deficiency of _______ in red and white blood cells and in liver cells
fibrous gliosis
Purkinje and granule cells
GALT
The treatment of galactossemia
is essentially________
dietary, using milk substitutes; if this is
instituted early, the brain should be protected from injury
Types of organic aciduria
Ketotic and non-ketotic
This is an autosomal recessive disease caused
by a primary defect in organic acid metabolism that is
expressed clinically by episodes of vomiting, lethargy,
coma, convulsions, hypertonia, and respiratory difficulty
the ketotic types, the main one is propionic
acidemia.
In Propionic acidemia:
______, ________, various forms of ______
and butanone are elevated in the serum
As with other
ketotic organic acidurias, ______ intake induces attcks
Propionic acid, glycine, fatty acids,
high protein
A number of other ketotic acidurias also occur in infancy.
The most important of these are _________. Each of
these disorders can become manifest with profound metabolic acidosis and intermittent lethargy, vomiting, tachypnea,
methtylmalonic acidemia,
isovaleric acidemia,
beta-keto acidemia, and
lactic acidemia
Rare subtypes of methylmalonic
acidemia respond to ________
vitamin B1 2•
________is characterized
by a striking odor of stale perspiration, which has
given it the sobriquet “sweaty foot syndrome.”
Isovaleric acidemia
The enzymatic defect of isovaleric acidemia also has been demonstrated in a recurrent form of _______ and ____ and in a persistent form in mitochondrial encephalopathies _________
episodic cerebellar ataxia and athetosis
Leigh dse
A___________ has also been observed
in the neonatal period and causes episodes of acidosis
with vomiting and hyperglycemia. Multiple congenital
anomalies of brain and somatic structures and cardiomyopathy are conjoined.
type II glutaric acidemia
In the _________ there are high
levels of glycine but no acidosis. The notable diagnostic
finding is an elevation of the CSF glycine, several times
higher than that of the blood.
The effects on the nervous
system are more devastating than in the ketotic form. I
nonketotic form of hyperglycinemia,
In nonketotic form of hyperglycinemia,
No treatment has been effective in severe cases.
In an atypical milder form, with neurologic abnormalities that appear in later infancy or childhood, reduction of dietary protein and administration of _______ in doses up to 250 mg/kg/ d have been beneficial.
The use of ____________
which blocks glycine receptors, is said to be
effective in preventing seizures and coma.
sodium benzoate
dextromethorphan,
These are a group of six diseases caused b y inborn deficiencies of the enzymes of the Krebs-Henseleit urea cycle; they are designated as
The pattern of inheritance of each of these disorders
is _________ except for OTC deficiency, which
is________
- N-acetyl glutamate synthetase,
- carbamoyl phosphate synthetase (CPS),
- ornithine transcarbamylase (OTC),
- argininosuccinic acid synthetase ( citrullinemia),
- argininosuccinase deficiency, and
- arginase deficiency
autosomal recessive
X-linked dominant.
____________ commonly appears during later childhood
as a progressive spastic paraplegia with mental retardation
arginase deficiency
what is a constant feature of hyperammonemia in less affected infants
respiratory alkalosis
CT scan of pts with hyperammonemia
brain edema may be seen by CT and MRl;
with repeated relapses, the brain edema gives way to atrophy; which appears as symmetrical areas of decreased attenuation in the cerebral white matter.
________ in which excessive dryness and brittleness of the hair (trichorrhexis nodosa) are notable features, and the aforementioned arginase deficiency with ______
argininosuccinic aciduria,
spastic diplegia.
Inherited hyperammonemia:
Diagnosis is established by the finding of hyperammonemia, often as high as _______.
1,500 mg/ dL
Inherited hyperammonemia:
In the acutely fatal cases, the brain is swollen and edematous, and the _____are diffusely
increased in number and enlarged. The neurons are __________
Astrocytic swelling has been attributed to the accumulation of glutamate secondary to a suppression of _______
astrocytes
normal.
glutamate synthetase.
As in all forms of liver disease,________and
other hepatic toxins may cause hepatic coma by further
impairing the urea cycle enzymes.
valproic acid
Treatment of the Hyperammonemic Syndromes
The treatment of acute hyperammonemic syndromes is
directed at lowering ammonia levels by hemodialysis,
exchange transfusions, and administration of ________
arginine
and certain organic acids.
Treatment of the Hyperammonemic Syndromes
Sodium benzoate should
be given in doses up to_______, supplemented by
________
250 mg/ d
sodium phenylacetate or sodium phenylbutyrate
_____ must be added to the diet as its deficiency causes MR and skin rashes
ARginine 50-150 mg/kg/day
These conditions are caused b y a deficiency o f a-keto
acid dehydrogenase, resulting in the accumulation of
the branched-chain amino acids leucine, isoleucine, and
valine
B r a n c h e d - C h a i n Am i n oa c i d o p at h i es ( M a p l e
Syru p U ri n e D i sease)
With the
most-severe neonatal type, the infant appears normal at
birth, but toward the end of the first week, poor feeding,
intermittent hypertonicity, opisthotonos, and respiratory
irregularities appear. Whta is the dse?
MSUD
inheritance of MSUD
AR
MSUD tests positively
for_______
2,4-dinitrophenylhydrazine (DNPH).
In MSUD
Secondary accumulation of a
derivative of _________ probably accounts
for the maple syrup odor.
a-hydroxybutyric acid
IN MSUD
The acute episodes, which threaten life, may
require _________ to remove the putative toxic
metabolites;
they respond to the administration of __________ mixtures that are free of branched-chain
keto acids.
peritoneal dialysis
glucose
amino acid
These are extremely rare autosomal recessive disorders of ________metabolism, manifest clinically during the neonatal period by seizures, axial hypotonia, reduced level of responsivity, and spasms with opisthotonos
sulfur
There are no differences
between pure sulfite oxidase deficiency and that
associated with _________
molybdenum cofactor deficiency
In the Dx of Neonata l Meta bolic Diseases
A history that_______are rejected by the infant, should raise the suspicion of an inherited hyperammonemic disorder or an organic acidemia.
protein foods
________ is one of the most frequent causes of neonatal seizures; tetany, spasms, and tremulous movements are usually present
Hypocalcemia
CSF _________ causing failure to thrive, severe
developmental disability with spasticity and intractable
epilepsy
serine transport
In H E R E DITARY M ETABOLIC DISEAS ES
O F I N FANCY, The most distinctive members of this category of neurologic disease are the__________and the__________
leukodystrophies
lysosomal storage diseases.
The _________ are a group
of inherited metabolic diseases of the nervous system
characterized by progressive, symmetrical, and usually
massive destruction of the white matter of the brain and
sometimes of the spinal cord
leukodystrophies
disorders an increased quantity of sphingolipid accumulated in the brain and other tissues.
sphaingolipidoses.
The _________are a class of intracellular lipids that all have ceramide as their basic structure, but each has a different attached oligosaccharide or phosphorylcholine.
Sphingolipids
Inheritance of Tay Sach
AR
Manifestation of TaySach:
The disease
becomes apparent in the first weeks and months of life,
almost always by the_______
fourth month.
In Tay Sach:
Degeneration of the macular cells exposes the underlying red vascular choroid surrounded by a whitish gray ring of retinal cells distended with ganglioside. The resulting appearance is of the _______
cherry-red spot
with optic atrophy
In Tay Sach
Cachexia becomes increasingly severe and
death occurs at ______
2 to 4 years
In Tay Sach
The basic enzymatic abnormality is a deficiency
of _________ which normally cleaves the
N-acetylgalactosamine from gangliosides.
beta hexosaminidase A,
In Tay Sachs
The brain is large, sometimes twice the normal
weight.
In addition, there is a loss of neurons and a reactive
gliosis; remaining nerve cells throughout the CNS are
distended with ________
glycolipid.
In __________, which affects infants of nonJewish
origins, there is a deficiency of both hexosaminidase
A and B, moderate hepatosplenomegaly, and coarse
granulations in bone marrow histiocytes.
Sandhoff disease
The onset of the neuronopathic form is usually before 6 months and frequently before 3 months.
The clinical course is
more rapid than that of Tay-Sachs disease (most patients
with infantile Gaucher disease do not survive beyond
1 year and 90 percent not beyond 2 years) .
I nfa nti le Gaucher Disease (Type I I
N e u ronopath i c Form , G l u cocerebrosidase
Deficien cy, G BA M utati o n )
I nfa nti le Gaucher Disease
The important laboratory findings are an increase
in serum acid phosphatase and characteristic histiocytes
called __________in marrow smears and liver and spleen
biopsies.
A deficiency of ______________ in leukocytes
and hepatocytes
(Gaucher cells)
glucocerebrosidase
what kind of cell:
20 to 60 um in diameter, with a wrinkled appearance of the cytoplasm and eccentricity of the nucleus
Gaucher cells
In contrast to the type II form described above, type
I Gaucher disease is a _________and relatively
benign form.
nonneuronopathic
It expresses itself in late childhood or adolescence
by a slowly progressive mental decline, seizures,
and ataxia, and, later, by spastic weakness and splenomegaly.
Vision and retinae remain normal.
Type III Gaucher
In Type III Gaucher
Highly diagnostic is
the defect in _________, with full movements
on the oculocephalic (“doll’s-head”) maneuver.
voluntary lateral gaze
This i s also an autosomal recessive disease. Two-thirds
of the affected infants have been of Ashkenazi Jewish
parentage.
I nfa nti le N i e m a n n -Pick Disease
Sph i n gomye l i n ase Deficiency, N PC M utati o n
I nfa nti le N i e m a n n -Pick Disease:
The onset of symptoms in the usual type A
disease is between________ of age, frequently
beginning with marked enlargement of liver, spleen, and
lymph nodes and infiltration of the lungs; rarely, there is
jaundice and ascites.
Cerebral abnormalities are definite by the _________ often earlier
3 and 9 months
end of the first year,
I nfa nti le N i e m a n n -Pick Disease:
____________in the bone marrow
and vacuolated blood lymphocytes are the important laboratory findings.
Vacuolated histiocytes (“foam cells “)
I nfa nti le N i e m a n n -Pick Disease:
A deficiency of _______ in leukocytes,
cultured fibroblasts, and hepatocytes is diagnostic.
sphingomyelinase
nfa nti le N i e m a n n -Pick Disease:
The most prominent
neuronal changes are seen in the ________
midbrain, spinal
cord, and cerebellum
This i s probably a n autosomal recessive disease without
ethnic predominance. The infants appear abnormal at
birth. They have dysmorphic facial features, like those of
the mucopolysaccharidoses:
Infa ntile Gen era l ized GM1 G a n g l i osidosis
(Type I, Beta-Galactosidase Deficiency,
Pseu d o - H u rler Disease, G L B 1 M utatio n
Other features of I nfa ntile Gen era l ized GM1 G a n g l i osidosis:
Loss of vision, coarse nystagmus and strabismus,
macular cherry-red spots (in half the cases), flexion
pseudocontractures of elbows and knees, kyphoscoliosis,
and enlarged liver and sometimes enlarged spleen are the other important clinical findings
I nfa ntile Gen era l ized GM1 G a n g l i osidosis:
A partial or complete deficiency of _________
and accumulation of _______ in the viscera and
in neurons and glia cells throughout the CNS are the
specific biochemical abnormalities.
beta-galactosidase
GM1 ganglioside
The onset is usually before the sixth month and often before the third month (10 percent after 1 year) .
Early manifestations are generalized rigidity, loss
of head control, diminished alertness, frequent vomiting,
irritability and bouts of inexplicable crying, and spasms
induced by stimulation.
G l o boid Cel l Leu kodystrophy ( Kra bbe
Disease, Galactocerebrosidase Deficiency,
GALC M utati o n )
In Kra bbe Disease, what are the signs added in later course of the dse
peripheral neuropathy
Other imaging features of Krabbe dse
enlargement of prechiasmatic ON
EMG findings of Krabbe:
is evidence of denervation and slowed motor and sensory
nerve conduction velocities, reflecting a ________
demyelinating
polyneuropathy
The deficient lysosomal enzyme in Krabbe disease is
galactocerebrosidase it normally degrades galactocerebroside to _______ and _____
ceramide and galactose
In Krabbe dse, a toxic metabolite,
________, leads to the early destruction of oligodendrocytes
and depletion of lipids in the cerebral white
matter.
psychosine
In what may be considered a possible breakthrough in
the treatment of childhood metabolic disease, Escolar
and colleagues reported the successful use of ___________________ in asymptomatic babies with Krabbe disease
transplanted umbilical cord hematopoietic cells
is a progressive encephalopathy punctuated by episodes
of more rapid deterioration
The denominative feature is a symmetrical leukodystrophy with progressive disappearance of white matter and replacement
by CSF or gliosis.
Va n is h i n g Wh ite M atter Disease
In Va n is h i n g Wh ite M atter Disease
The affected gene encodes_____________ one of the two myelin basic proteins
proteolipid protein
(PLP),
Initial abnormality in Vanishing WM dse
The first signs are abnormal movements of the eyes (rapid, irregular, often asymmetrical pendular nystagmus), jerk nystagmus on extremes of lateral movements, upbeat nystagmus on upward gaze, and hypometric saccades
An interesting but unexplored aspect of the disease is the occurrence of blond hair and light complexion in affected members, in contrast to the darker hair and complexion of their normal siblings
Spongy Degeneration of I nfa ncy (Ca n ava n va
n Bogaert- Bertra n d or Ca n ava n Disease,
ASPA M utation)
In Canavan’s dse, The disease is characterized by
an increased urinary excretion of __________which may be used as a biochemical marker
N-acetyl-L-aspartic acid
(NAA),
Canavan’s dse CT
On CT there is attenuation of cerebral and
cerebellar white matter in an enlarged brain with relatively nonnal-size ventricles.
what dse?
A leukodystrophy with behavioral
regression, an enlarging head, a characteristic MRI
abnormality, and a marked elevation of urinary NAA
should leave little doubt about the diagnosis.
Canavan’s dse
The onset is in infancy with a failure to thrive, psychomotor retardation, spasticity of the craniospinal m usculature, and seizures.
An early and progressive macrocephaly has been a
consistent feature.
Alexa nder Disease ( G FAP M utati o n )
Pathology of Alexander’s dse
the extensive loss of cerebral white matter, and highly characteristic inclusion in astrocytes,
and subpial and periventricular regions called _________
Rosenthal fibers
This i s a progressive disease o f the cerebral gray matter,
known also as progressive cerebral poliodystrophy or diffuse cerebral degeneration in infancy
Al pers Disease ( PO LG M utatio n )
A number of biochemical abnormalities have been
identified in patients with Alpers disease, including
____________deficiency, decreased pyruvate
utilization, dysfunction of the citric acid cycle,
and decreased cytochromes a and aa3
pyruvate dehydrogenase
