Term
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Definition
Chromosomal inheritance
Trisomy 21
Impairment of cognitive ability & physical growth and a particular facies; (a particular set of facial characteristics that are associated with a disease)
Ventricular septal defect
Mental Retardation
Predisposition to hematologic malignancies
Infertility
hypothyroidism |
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Term
| Velocardiofacial Syndrome (DiGeorge S) |
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Definition
Autosomal Dominant
Deletion of long arm of chromosome 22
Classified as a Recurrent Genomic disorder due to a lot of high identical repeats
This causes migration defects of neural crest-derived tissues
Particularly 3 and 4th branchial pouches
Birth defects such as congenital heart disease, defects in the palate, most commonly related to learning disabilities, mild differences in facial features, and recurrent infections
Cardiac abnormality (Especially tetralogy of fallot)
Abnormal faces
Thymic aplasia
Cleft palate
Hypocalcemia
Mental retardation |
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Term
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Definition
Autosomal Dominant
Mutation in the fibroblast growth factor receptor gene 3 (FGFR3) making it constituitively active, leading to abnormality of cartilage formation
Very prominent stature, face and hand abnormalites frontal bone protrusion
Dwarfism
Frontal bossing (frontal bone protrusion)
Lordosis
Trident Hand
Sickle Cell Disease |
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Term
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Definition
Autosomal Recessive
A point mutation in the β-globin chain of haemoglobin, causing the hydrophilic AA glutamic acid to be replaced with the hydrophobic AA valine at the sixth position;
found on chromosome 11
Several vascular symptoms ultimately leading to splenic and bone crises
Vaso-occlusive crisis
Stroke
Splenic sequestration
Vaso-oclusion of vessels out of the spleen, blood stays in the spleen, it enlarges. Hemoglobin and hematocrit plummet.
Can be painful
Sepsis (due in part to splenic sequestration)
Anemia (also in part to splenic sequestration), a milder form of:
Aplastic Crisis (lack of reticulocytes),
Pain
Bone Infarcts |
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Term
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Definition
Autosomal Dominant
Mutation of a gene on chromosome 17, encoding neurofibromin; a negative regulator of the Ras oncogene
NF1 loss leads to increased RAS signaling (laymen’s terms)
NF-1 is a tumor disorder
Varying severity of neoplastic abnormalities, neurologic and skeletal symptoms
Freckles
Café au lait spots
bony lesions
scoliosis
epilepsy
learning difficulties
glioma |
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Term
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Definition
Chromosomal
Seven genes (or some subset thereof) on paternal chromosome 15 are deleted or unexpressed due to an imprinting mutation or uniparental disomy
Large but short children with dysmorphic facies
Hypotonia
A state of low muscle tone (may be neurologic or skeletal)
Failure to Thrive
Childhood Onset Hyperphagia
Dysmorphic Facies/Habitus
Mild-Moderate Mental R.
Endocrine Dysfunction
Insulin
Growth Hormone |
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Term
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Definition
Chromosomal
Deletion, uniparental disomy, translocation or single gene mutation on maternal chromosome 15 (Angelman)
Large children with dysmorphic facies and cartoon-like episodes of behavior/ “puppet syndrome”
Hypotonia
Failute to thrive
Childhood onset obesity
Dysmorphic facies
Severe MR
Neurologic Dysfunction (causing the ‘puppet syndrome’)
Hyperflexia
Tremor
Ataxia
Paroxysmal Laughter |
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Term
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Definition
Autosomal Dominant or Recessive (because of locus heterogeneity)
Recessive is more serious
A mutation in one of several genes results in prolonged duration of the ventricular action potential lengthening of the QT interval
Cardiac symptoms similar to those seen in arhytmias
Increased risk of torsade de pointes
Palpitations
Fainting
Sudden Death to to Ventricular Fibrilation |
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Term
| Duchenne Muscular Dystrophy |
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Definition
X-Linked
Mutation of the dystrophin gene at locus Xp21. Dystrophin is responsible for connecting the cytoskeleton of each muscle fibers to the underlying basal lamina (extracellular matrix) through a protein complex containing many subunits. The absence of dystrophin permits excess calcium to penetrate the sarcolemma (cell membrane). In a complex cascading process that involves several pathways and is not clearly understood, increased oxidative stress within the cell damages the sarcolemma, and eventually results in the death of the cell. Muscle fibers undergo necrosis and are ultimately replaced with adipose and connective tissue
Rapid progression of muscle degeneration, eventually leading to loss of ambulation and death
Progressive neuromuscular disorder
Affects voluntary muscles first
Can start in infancy
Affected individuals often in wheelchair by |
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Term
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Definition
Autosomal Recessive
Chloride channel dysfunction leading to thick viscous secretions
Affects several mucorelated systems; pulmonary, GI and GU
Persistent pulmonary infection
Pancreatic Insufficiency
Clumpy smelly stools
Elevated sweat chloride levels (diagnostic)
azoospermia |
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Term
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Definition
Autosomal Dominant (Full penetrance at repeat sizes > 38)
Trinucleotide disorder (Codon repeat/small tandem repeat)/expansion of CAG unit.
This results in genetic instability although the mechanism is poorly understood.
Anticipation is the phenomenon of expansion of repeats between generations leading to earlier and more severe phenotype. Expansions occur predominantly in men
This is a neuromuscular disorder with movement and neural problems
Progressive movement disorder
Chorea “Dance-like movements”
Dementia
Seizures
Atrophy of Caudate Nucleus |
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Term
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Definition
Autosomal Recessive
o Phenylalanine Hydroxylase Deficiency (the enzyme responsible for the conversion of the essential amino acid phenylalanine to tyrosine resulting in a buildup of Phenylalanine and no production of tyrosine and its derivatives; dopamine and melatonin)
o Severe mental retardation and other neurologic problems Severe Irreversible Mental Retardation Behavioral problems Hypopigmentation Seizures |
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Term
| Tetrahydrobiopterin (BH4) deficiency |
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Definition
| Autosomal Recessive o Deficiency of BH4 the cofactor responsible for tyrosine hydroxilase, tryptophan hydroxilase. This deficiency leads to accumulation of Phenylalanine and decreased production of Dopamine, Epinephrine, Norepinephrine, Serotonin and NO o CX Similar to PKU but can be more severe |
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Term
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Definition
| o Autosomal Recessive o Mutation in both copies of the PCCA or PCCB genes responsible for the enzyme Propionyl CoA Carboxylase Propionyl CoA Carboxylase Deficiency thus there is a buildup of Propionyl CoA resulting in increased Propionic Acid and a buildup of the essential amino acids that go into propionyl coa (Val, OCF, Met, Iso, Thr) o Build up of organic acids and amino acids resulting in metabolic acidosis, and other metabolic abnormalities leading to delayed development and neurologic symptom Anion Gap Metabolic Acidosis • There are two types of Metabolic Acidosis High anion gap which results from an accumulation of non-volatile organic acids and normal anion gam metabolic acidosis which results from a net loss of bicarbonate e.g Diarrhea Hyperammonemia • Propionyl CoA inhibits the Urea Cycle Hyperglycenimia • Propionyl CoA inhibits Glycine cleavage Vomiting Lethargy Coma Death Failure to thrive Developmental delays |
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Term
| Ornithine Transcarbamylase Deficiency (OTC) |
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Definition
| X-Linked (recessive) o Deficiency in Ornithine Transcarbamylase Responsible for converting ornithine + carbamyl phosphate to citruline. Without this there is an accumulation of ammonia o Affects the body’s ability to get rid of ammonia resulting in neurological symptoms and blood pH abnormalities Typically presents when babies first eat (72h) Vomiting Encephalopathy High Ammonia Respiratory Alkalosis • Males have 70% mortality • Females usually ok with a milder phenotype • Males possible to have a milder phenotype (like that 16 year old he talked about in class) |
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Term
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Definition
| o Autosomal Recessive o GALT deficiency (Galactose-1-phospate uridyl transferase) the enzyme responsible to convert Galactose-1-P to UDPgalactose o Buildup of Galactose which causes diffuse symptoms in the following systems; Hematologic, Ocular, Hepatic, Neuro and GU Newborn coagulopathy Liver Disfunction/failure Cataracts E.COLI SEPIS Primay ovarian failure Learning disabilities |
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Term
| Glycogen Storage Disase, type 1a |
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Definition
| Autosomal Recessive o Glucose-6-Phosphatase Deficiency (Can’t break down glycogen into glucose) o Symptoms involve inability to mobilize glycogen, leading to decreased energy lethargy, liver disease and associated liver function disorders (hypertriglyceridemia) SEVERE Hypoglycemia Hyperuricemia Gout (G6P bleeds over to Uric acid via PPP) Hypertriglyceridemia Pancreatitis (G6P Puryvate Triglycerides) Liver adenomas tumors Hepatomegaly (From excess glycogen) Renal Disease (From Uric Acid Stones |
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Term
| Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD) |
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Definition
| Autosomal Recessive o Deficiency in Medium-chain acyl-coenzyme A dehydrogenase Can’t metabolize medium chain fatty acids o The symptoms are Gastrointestinal in nature with an associated hyperammonemia that results in neurologic damage. The most striking phenomenon is Hypoktotic Hypoglycemia Fasting HYPOKETOTIC HYPOGLYCEMIA Responsible for SIDS (sudden infant death syndrome) Liver Disease with Hyperammonemia • Reye-like Symptoms • Hepatomegaly • Acute liver disease Neurologic • Lethary, Coma, Seizures |
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Term
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Definition
| Autosomal Recessive o Lysosomal Storage Disease (most common) GBA/glucocerebrosidase deficiency Affects recycling of Glucosylceramide/glucocerebroside o As glucocerebroside can collect in the spleen, liver, kidneys, lung, brain and bone marrow it can be pan-systemic • Hepatosplenomegaly • Bone Marrow Disease o Pancytopenia o Thrombocytopenia • Skeletal Disease o Osteopenia and pathologic fractures o Bone Pain (similar to sickle cell crisis) o Osteonecrosis/ bone infarcts o Vertebral compression o ERENMYER FLASK deformity of Femer Type I • Ashkenazi • Non-neuropathic • Mostly visceral and skeletal disease Type II • Neurodegenerative, fatal by ~2 years of age Type III • Intermediate • More common in Swedes |
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Term
| MELAS (Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Episodes |
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Definition
o Maternal, Mitochondrial
Inheritance Heteroplasmy = differing concentration of good to bad mitochondria resulting in a statistically random inheritance and severity of disease. incalculable recurrence risk because of random good and bad mitochondrial ratios
The opposite is homoplasmy where all the mitochondria within a cell share the same genome
Threshold Effect • This indicates that there is a certain percentage/ ratio of good to bad mitochondria at which disease can be seen.
Replicative Segregation • Mitochondria are partitioned along with the cytoplasm during cell division. The distribution of mutant and normal molecules in the daughter cells of heteroplasmic cell may be unequal. In the course of development and differentiation, different parts of the body may have different proportion of mutant molecules. Different tissues get different proportions of good-bad mitochondria. This results because of Heteroplasmy and random mitochondrial assortment during cytokinesis •
o Specifically a mutation in the mitochondrial genes for NADH dehydrogenase and nuclear gene MT-TL1. Problem in any of the mitochondrial or nuclear genes responsible for functional electron transport chain will cause similar disorders. o
Symptoms are often multi-system (as are many mitochondrial diseases) most common are muscular and neurologic problems accompanied by Lactic Acidosis (no krebs cycle or ETC) Lactic Acidosis Myopathy
• Exercise intolerance Cardiomyopathy Hepatopathy Developmental Delay Deafness Blindness Stroke-like episodes Diabetes Mellitus/insipidus Short Stature Tonic Clinic Seizures Hemiparesis o Cortical blindness Headaches Anorexia Vomiting • Altered consciousness
Residual effects may gradually impair following abilities by young adulthood o motor abilities o vison o mentation o Sensorineural hearing loss is common |
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Term
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Definition
| o Autosomal Dominant Inheritance Pattern o FBN1 mutation, the gene responsible for fibrillin-1 Large gene, majority of patients o TGFBR mutation Minority of patients o Molecular mechanism is not well understood but is believed to involve fibrillin-1 important protein component in both elastic and nonelastic connective tissue. Most specifically in elastin containing matrix; aorta, tenoligament and ciliary zonules of the eye TGF-beta theory says that there may be an increased bioavailability of TGF-beta o Clinical symptoms often involve skeletal, cardiovascular and ocular systems (tissues with abundant type I collagen) Occular • Myopia; Displacement of the lens from the center of the pupil • Increased risk for glaucoma, retinal detachment, cataracts Cardiovascular • Dilatation of the Aorta (@ sinus of valsalva) • Aortal tear, rupture, dissection • Mitral prolapse • Tricuspid valve prolapse Skeletal • Bone overgrowth • Joint laxity • Long limbs (dolichostenomelia) • Rib overgrowth can deviate the sternum o Pectus excavatum (sternum pushed in) o Pectus carinatum (sternum pushed out) • Scoliosis (lateral curvature of the spine) |
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