·         Impaired cognition and physical growth

·         Facies (characteristic facial feature)

·         Ventricular septal defect

·         Mental retardation

·         Predisposition to hematologic malignancy

·         Infertility

·         Hypothyroidism

·         Splenic and bone crises

·         Vaso-occlusive crisis

o   Stroke

o   Splenic sequestration (can be painful)

§  Hemoglobin and hematocrit levels drop

o   Anemia

o   Aplastic Crisis (lack of reticulocytes)

o   Pain

o   Bone Infarcts

o   Functional asplenia

·         Mutation of neurofibromin gene on chr. 17

·         NF negatively regulates Ras (oncogene)

·         Loss of NF à increased Ras signaling

·         Variable expressivity

·         Freckles

·         Café au lait spots

·         Bony lesions

·         Scoliosis

·         Epilepsy

·         Learning difficulties

·         Glioma

·         Large, short children with dysmorphic facies

·         Hypotonia (low muscle tone)

·         Failure to thrive

·         Chid-onset hyperphagia

·         Mild to moderate mental retardation

·         Endocrine dysfunction

o   Insulin

o   Growth hormone

·         A single gene on maternal chr. 15 is deleted/silenced via imprinting, uniparental disomy, translocation, or mutation

·         Large children, dysmorphic facies and “puppet syndrome”

·         Hypotonia

·         Failure to thrive

·         Child-onset obesity

·         Severe mitral-regurge

·         Neurologic Dysfunction (“puppet”)

o   Hyperflexia

o   Tremor

o   Ataxia

o   Paroxysmal laughter

·         Locus Heterogeneity

·         Mutation in several genes leads to prolonged ventricular action potential (increased QT interval)

·         Cardiac symptoms

o   Increased risk of torsade de pointes

o   Palpitations

o   Fainting

o   Sudden death (ventricular fibrillation)

·         Mutation of dystrophin gene at locus Xp21

·         Absence of dystrophin à calcium influx à sarcolema damage à muscle cell/fiber death and replaced by adipose and connective tissue

·         Rapid muscle degeneration, loss of ambulation (death)

·         Progressive neuromuscular disorder (voluntary first)

·         Can start in infancy

·         Pulmonary, GI, GU involvement

·         Persistent pulmonary infection

·         Clumpy, smell stool

·         Elevated sweat chloride levels (salty sweat)

·         Azoospermia (e.g. lack of vas deferens)

·         100% penetrance

·         Progressive neural and muscular problems

·         Chorea “dance-like movements”

·         Dementia

·         Seizures

·         Atrophy of caudate nucleus

·         Build-up of phenylalanine leads to severe mental retardation and other neural conditions

·         Behavioural problems

·         Hypopigmentation

·         Seizures

·         Definiciency of BH4, which is cofactor for tyrosine hydroxilase, tryptophan hydroxilase

·         Accumulation of Phenylalanine and decrease dopamine, epinephrine, norepinephrine, serotonin, NO

·         Build-up of phenylalanine leads to severe mental retardation and other neural conditions

·         Behavioural problems

·         Hypopigmentation

·         Seizures

·         Mutation in both copies of PCCA or PCCB (code for Propionyl CoA Carboxylase)

·         There is enzyme deficiency à buildup of propionyl CoA à buildup of propionic acid and buildup of essential amino acids (Val, Met, Iso, Thr)

·         Metabolic acidosis, delayed developed, neurological symptoms

·         High Anion gap (accumulation of non-volatile organic acids)

·         Normal anion gap (net loss of bicarbonate)

·         Hyperammonemia (Propionyl CoA inhibits Urea Cycle)

·         Hyperglycenimia (Propionyl CoA inhibits Glycine cleavage)

·         Vomiting

·         Lethargy à Coma à Death

·         Failure to thrive

·         Neurlogic symptoms and blood pH abnormal

·         Typically presents when babies first eat (72hr)

·         Vomiting

·         Encephalopathy

·         High ammonion

·         Respiratory alkalosis

·         70% mortality in males, females usually okay with milder phenotype

·         Hematologic, Ocular, Hepatic, Neuro, and GU presentations

·         Newborn coagulopathy

·         Liver Dysfunction/filure

·         Cataracts

·         E.Coli Sepsis

·         Primary ovarian failure

·         Learning disability

·         Decreased energy (can’t mobilize glycogen stores), lethargy, liver disease, hypertriglyceridemia

·         Severe Hypoglycemia

·         Hyperuricemia à Gout (G6P becomes Uric acid)

·         Hypertriglyceridemia à Pancreatitis (G6P à Pyruvate à Triglycerides)

·         Liver adenomas

·         Hepatomegaly

·         Renal Disease (uric acid stones)

·         GI symptoms with associate hyperammonemia leading to neurologic damage

·         Fasting Hypoketotic Hypoglycemia

·         Responsible for Sudden Infant Death Syndrome

·         Liver Disease

o   Reye-like symptoms

o   Hepatomegaly

o   Acute Liver Disease

·         Neurologic (lethary, coma, seizures)

·         Glucocerebroside can collect in spleen, liver, kidneys, lung, brain, and bone marrow, so can be pan systemic

o   Hepatosplenomegaly

o   Bone marrow disease (pancytopenia, thrombocytopenia)

o   Skeletal disease (osteopenia, fractures)

§  Bone pain

§  Osteonecrosis/bone infarcts

§  Vertebral compression

§  Erlenmyer flask deformity of femur

·         Type I

o   Ashkenazi Jews

o   Non-neuropathic

o   Mostly visceral and skeletal disease

·         Type II

o   Neurodegenerative, fatal by 2 years of age

·         Type III

o   Intermediate

o   More common in Swedes

·         Heteroplasmy due to ratio of good/bad mitochondria across cells, tissues, etc.

·         Variable inheritance and severity of disease

·         Threshold effect – need to cross certain ratio of good/bad mitochondria to see symptoms/signs

·         Due to mutation in mitochondrial gene for NADH dehydrogenase and nuclear gene MT-TL1

·         Similar disorders can occur due to any other problems in mitochondrial or nuclear genes responsible for function electron transport chain

·         Multi-system disorder (most common are muscle and neurologic problems accompanied by Lactic Acidosis (build up of Lactic Acid since there’s 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 clonic seizure (hemiparesis, cortical blindness)

·         Headaches

·         Anorexia

·         Vomiting

·         Altered consciousness

·         FBN1 mutation (gene responsible for fibrillin-1) - majority

·         TGFBR mutation – minority

·         The above is example of locus heterogeneity – mutations on different genes give you same disease

·         Fibrillin-1 is important in elastic and non-elastic connective tissue (elastin containing matrix, aorta, tenoligament, and ciliary zonules of the eye)

·         TGFBR – increased bioavailability of TGF-beta

·         Clinical signs involve skeletal, cardiovascular, and ocular systems (tissues with abundant type 1 collagen)

·         Ocular

o   Myopia (lens displacement from center of pupil)

o   Increased risk for glaucoma, retinal detachment, cataracts

·         Cardiovascular

o   Dilatation of aorta

o   Aortic tear, rupture, dissection

o   Mitral prolapsed

o   Tricuspid valve prolapse

·         Skeletal

o   Bone overgrowth

o   Joint Laxity

o   Long Limbs (dolichostenomelia)

o   Rib overgrowth can lead to deviated sternum

§  Pectus excavatum (pushed in)

§  Pectus carinatum (pushed out)

o   Scoliosis