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,
