Inherited Metabolic Diseases Flashcards
number of mitochondrial genes
37
homoplasmy
the presence of either completely normal or completely mutant mitochondrial DNA
of the five complexes that make up the respiratory chain, _____________ or complex ____, is the one most often disordered and its deficient function gives rise to lactic acidoses
cytochrome-c oxidase
complex IV
The first definite indication of disordered nervous system function is likely to be the occurrence of
seizures
three most frequently identified hereditary metabolic diseases that do not become clinically manifest in the neonatal period
phenylketonuria
hyperphenylalaninemia
congenital hypothyroidism
vitamin-responsive aminoacidopathy
autosomal recessive
early onset of convulsions, sometimes in utero
failure to thrive, hypertonia-hyperkinesia, irritability
tremulous movements
exagerated auditory startle
psychomotor retardation
increased excretion of xanthurenic acid in response to tryptophan load
decreased levels of pyridoxal-5-phosphate and GABA in brain
mutation: ALDH7A1 gene
Pyridoxine-dependent seizures
treatment: 50-100mg of Vitamin B6 suppresses the seizure state and daily doses of 40mg permit normal development
some patients with increased concentrations of phenylalanine in the neonatal period are unresponsive to measures that lower phenylalanine
if not treated promptly will lead to seizures - myoclonic and grand mal types, poor level of responsiveness, generalized hypotonia
swallowing difficulty
normal levels of phenylalanine hydroxylase enzymes
there is a lack of cofactor for phenylalanine hydroxylase (cofactor of phenylalanine hydroxylase)
Biopterin deficiency
treatment: tetrahydrobiopterin in a dosage of 7.5mg/kg/d in combination with a low-phenylalanine diet
dx: urine pterins
Autosomal recessive
defect in Galactose-1-phosphate uridyl transferase (GALT)
the enzyme which catalyzes the conversion of galactose-1 phosphate to uridine diphosphate galactose
onset after first days of life, after ingestion of milk
vomiting and diarrhea and followed by failure to thrive
drowsiness, inattention, hypotonia,
fontanels may bulge, the liver and slpeen enlarge, skin becomes yellow, anemia
dxs: elevated blood galactose level
low glucose
galactosuria
deficiency of GALT in red and white blood cells, liver cells
Galactosemia
treatment: dietary, milk substitues
Beta Galactosidase deficiency
GM1 gangliosidosis
N-acetylhexosaminidase alpha subunit deficiency
Tay Sachs Disease
N-acetylhexosaminidase beta subunit deficiency
Sandhoff disease
GM2 activator deficiency
Acitivator Deficiency
arylsulfatase (sulfatidase), sulfatide activator (saposin B) deficiency
Metachromatic Leukodystrophy
galactocerebrosidase deficiency
Krabbe
Alpha galactosidase A deficiency
Fabry disease
Glucocerebrosidase deficiency
Gaucher disease
sphingomyelinase deficiency
Type A and B Niemann Pick Disease
Ceramidase deficiency
Farber Disease
Alpha Galactosidase B deficiency
Schindler Disease
deficiency of alpha keto acid dehydrogenase
resulting in accumulation of branched-chain amino acids leucine, isoleucine, valine
autosomal recessive
Maple Syrup Urine Disease
urine test for MSUD
2,4 dinitrophenylhydrazine DNPH
seizures, tremulousness, drowsiness occur with blood sugar levels less than
mature infant:
premature:
mature less than 30mg/dL
premature 20mg/dL
hallmark of all the hereditary metabolic diseases
psychosensorimotor regression
autosomal recessive
disease becomes apparent in the first weeks and months of life - almost always on the 4th month
regression of motor activity and an abnormal startle to acoustic stimuli, listlessness, irritability, poor reactions to visual stimuli
hypotonia then later spasticity
degeneration of macular cells - cherry red spot
Tay Sachs Disease
deficiency of N-acetylhexosaminidase a subunit
accumulation of GM2 gangliosides
brain is large
loss of neurons
remaining nerve cells are distended with glycolipid
autosomal recessive
before 6 months, frequently before 3
oculomotor apraxia, strabismus, rapid loss of head control, ability to roll over and sit, apathy, irritability, frequent crying, difficulty in sucking and swallowing
increase in serum acid phosphatase, characteristic histiocytes in marrow smears and liver and spleen biopsies
deficiency of glucocerebrosidase
accumulation of glucocerebroside
Infantile Gaucher Disease Type II
most patients do not survive beyond 1 year
90 percent not beyond 2 years
autosomal recessive
mutation in ASAH1
The onset is in the first weeks of life, with a hoarse cry because of fixation of laryngeal cartilage, respiratory distress, and sensitivity of the joints, followed by characteristic periarticular and subcutaneous swellings and progressive arthropathy, leading to ankylosis
ceramidase deficiency
Farber disease
Lipogranulomatosis
spongy degeneration of the brain
autosomal recessive
onset first neonatal weeks to first 3 months of life
rapid psychomotor function regression, loss of sight and optic atrophy, lethargy, difficulty sucking, irritability, reduced motor activity, hypotonia followed by spasticity, macrocephaly
sensorineural hearing loss, seizures
blond hair and fair complexion opposed to dark. haired sibling
increased urinary NAA
deficiency of aminoacylase II
CT imaging: attenuation of cerebral and cerebellar white matter with enlarged brain
Spongy Degeneration of Infancy
Canavan Disease
pathognomonic sign of wilson disease or hepatolenticular degeneration
Kayser-Fleischer rings
initial event in Wilson disease
deposition of copper in the liver leading to an acute or chronic hepatopathy and eventually to multilobular cirrhosis and splenomegaly
T/F
wilson disease.
The first neurologic manifestations are most often extrapyramidal with proclivity to affect the oropharyngeal musculature.
true
T/F
Wilson disease.
The kayser-fleischer rings are virtually always present once the neurologic signs become manifest.
true
T/F
The parkinsonian features of wilson disease are responsive to levodopa.
false
