INHERITED METABOLIC DISEASES Flashcards by MA CARMELA CONCEPCION SALES

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

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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

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3 types of Mendelian inheritance

AD, AR, Sex-linked

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An
individual, with both normal cells and cells containing the
mutant gene, is referred to as a _______

mosaic.

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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

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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

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__________ (“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

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How many of the mitochondrial genes partake in cellular process of oxidative phosphorylation?

13/37

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The essential feature of mitochondrial genes and the
mutations to which they are subject is that they are inherited
almost exclusively through _______

maternal lineage.

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mitochondria with mutant genes
may exist next to normal mitochondria , a
state that permits an otherwise lethal mutation to persist

heteroplasmy

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mechanism of mitochondrial DNA replication

there are contributions during cell division
from the genes of various mitochondria to the progeny of
dividing cells

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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)

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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.

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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

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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

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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

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Initial clues to metabolic disease

difficulties in feeding

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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

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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

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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 retardation

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Pyridoxine 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

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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

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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

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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.

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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________

1. N-acetyl glutamate synthetase, 2. carbamoyl phosphate synthetase (CPS), 3. ornithine transcarbamylase (OTC), 4. argininosuccinic acid synthetase ( citrullinemia), 5. argininosuccinase deficiency, and 6. 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

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

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