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Clinical manifestations of Mitochondrial Disease

-Basal ganglia lesions
-Encephalopathy - hepatopathy
-Cognitive decline
-Ocular signs (ptosis, optic nerve atrophy, retinopathy)
-Sensorineural hearing loss


Genetic of mitochondrial disease

37 genes encode 13 proteins and 24 RNAS

More than 200 nDNA-encoded mito genes - encode over 1500 proteins

Circular mitome

100 known mito disease genes

Defects affect the ETC (electron transport chain/respiratory chain)


mtDNA syndromes

MELAS - Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes

MERRF - Myoclonic epilepsy with ragged red fibers

NARP - neuropathy, ataxia, retinitis pigmentosa

MILS - maternally inherited Leighs syndrome

LHON - Leber's hereditary optic neuropathy

KSS/Pearson - sideroblastic anemia, pancreatitis (caused by mtDNA deletions)



Percentage of affected mitochondria determines severity of phenotype

High percentage - more severe phenotype

Low percentage - may not exhibit any phenotype

ex. T8993G mutation-carrying individuals appear normal from 0-60% affected DNA, have retinitis pigmentosa from 60-75%, have NARP from 75-90%, and have Leighs syndrome if 90% or more of the mitochondria is affected


Fission and Fusion (mitochondria dynamics)

Mitochondria replicate by fission, require fusion to operate
Several genes regulate this and gene defects lead to mitochondrial disease

-OPA1 - AD Optic Atrophy
-MFN2 - AD axonal variant Charcot-Marie-Tooth


Coenzyme Q10 Deficiency

6 Major clinical phenotypes
-Encephalomyopathic form with seizuers and ataxia
-Multisystem infantile form with encephalopathy, cardiomyopathy, and renal failure
-Predominantly cerebellar form with ataxia and cerebellar atrophy
-Leigh syndrome with growth retardation
-Isolated myopathy
-Steroid resistant nephrotic syndrome

May respond dramatically to Coenzyme Q10 treatment


mtDNA depletion syndrome symptoms

-Lactic acidosis in neonatal/childhood period
-Failure to thrive
-Muscle weakness in childhood and adulthood
-Ataxia in adulthood
-Polyneuropathy in adulthood
-Liver impairment in childhood
-Migrane-like headaches in juvenile period
-Developmental delay/cognitive impairment
-Psychiatric symptoms in teens and adulthood
-GI symptoms in adulthood


Defects of intergenomic communication

Mitochondrial neuro gastrointestinal encephalomyopathy
-pstosis and opthalmoplegia
-GI dysmotility
-peripheral neuropathy


Mitochondrial Disease Therapeutics

-Therapy based on specific pathway of respiratory chain affected

-Three parent children - Mitochondrial genome transfer to avoid mitochondrial diseases

-Gene therapy to reduce mutant mtDNA


Ammonia excretion - non-hepatic tissues

-Glutamate dehydrogenase and glutamine synthetase remove 2 ammonia molecules from tissues to rid them of nitrogen waste
-Glutamine deposits ammonia in kidney for excretion


Urea excretion - hepatic tissues

Requires water
Nitrogen waste ends up in urea
Goes into urea cycle
Amino acids derived either from breakdown of protein in tissues or from what is synthesized in those tissues



Acquired - liver disease leads to portal systemic shunting

Inherited - Urea cycle enzyme defects of CPS1 (carbonyl phosphate synthetase 1) or ornithine transcarbamylase lead to severe hypoammonemia


Metabolic functions of the liver

-Production and storage of glycogen
-Catabolism of glycogen to glucose
-Conversion of excess glucose to fat
-Transport of lipids/glucose to other tissues
-Conversion of ammonia to urea


Deammination as a source of ammonia production

Removal of an amino group from amino acids results in the production of an ammonia molecule


Non-IEM causes of Hyperammonemias

-Drug-related (valproate)
-Acute liver failure
-Reye syndrome
-Massive tissue necrosis
-Chronic UTIs with urine retention
-Overgrowth of bowel flora
-Portocaval shunts
-Transient hyperammonemia in newborns


Urea cycle functions

-Prevents the accumulation of toxic nitrogenous compounds by removing nitrogen through urea
-Contains several biochemical reactions for the de novo synthesis of arginine


Urea Cycle Disorders

-Carbamyl phosphate synthetase deficiency
-Ornithine transcarbamylase deficiency (most common)
-Argininosuccinic acid synthetase deficiency
-Argininosuccinic acid lyase deficiency
-Arginase deficiency (lease common)

Characterized by hyperammonemia, encephalopathy (due to accumulation of glutamine in the astrocyte), respiratory alkalosis


N-Acetylglutamate Synthase deficiency (NAGS)

-Autosomal recessive
-Lethargy, persistent vomiting, poor feeding, hyperventilation, enlarged liver, seizures
-Total deficiency - symptoms appear immediately following birth
-Partial deficiency - may occur later in life following a stressful event such as infection
-Low cirtulline levels, normal orotic acid levels


Carbamyl phosphate synthetase deficiency (CPS)

-Autosomal recessive
-Lethargy, coma, seizures, vomiting, poor feeding, hyperventilation, heptaomegaly
-Total deficiency - symptoms appear immediately following birth
-Partial deficiency - symptoms appear in childhood
-Low citrulline levels, normal orotic acid levels


Ornithine transcarbamylase deficiency

-Most common
-Lethargy, coma, seizures, vomiting, poor feeding, hyperventilation, hepatomegaly
-Hemizygote males - onset immediately after birth
-Hemizygote females - 10% are symptomatic
-Low citrulline levels, high orotic acid levels


Argininosuccinic acid synthetase deficiency (ASS)

-Autosomal recessive
-Lethargy, coma, seizures, vomiting, hyperventilation, poor feeding, hepatomegaly
-Total deficiency - symptoms appear immediately following birth
-Partial deficiency - symptoms appear in childhood
-High citrulline levels, high orotic acid levels


Argininiosuccinic acid lyase deficiency (ASL)

-Autosomal recessive
-Lethargy, coma, seizures, vomiting, hyperventilation, poor feeding, hepatomegaly
-Total deficiency - symptoms appear immediately following birth
-Partial deficiency - symptoms appear in childhood
-High citrulline levels, high orotic acid levels


Arginase Deficiency (ARG)

-Autosomal recessive
-Delayed development, protein intolerance, spasticity, seizures, irritability, vomiting, poor appetite
-Slower onset, often present with symptoms of muscle weakness, hyperammonemia is rare
-High citrulline levels, high orotic acid levels


Treatment of Urea Cycle Defects

-Goal is to maintain plasma glutamine levels at or near normal (Glutamine represents a storage form of nitrogen that can buffer ammonium)

-Measure of plasma glutamine levels may be single best guide to therapy (levels can predict hyperammonemia)

-Restricted intake of dietary protein

-Activation of other waste nitrogen pathways - CPS, OT, ASS - sodium phenylbutyrate activates phenylacetylglutamine - new vehicle for removal of waste nitrogen

-Arginine supplementation in ASS and ASL

-Ammonul medication

-Liver transplant in severe phenotypes


Functions of the lymphatic system

-Anatomic organization
-Fluid homeostasis
-Local tissue inflammation and edema
-Infection management
-Organ rejection


Lymphatic development

1. Embryonic veins express high levels of VEGFR-3 while a subpopulation of endothelial cells in large central veins express LYVE-1
2. SOX-18 transcription factor is induced in LYVE-1 positive cells
3. VEGFR-3 is downregulated in veins but remains high in lymphatic endothelial cell (LEC) precursors
4. LEC precursors express neutrophilin-2 which makes them more responsive to VEGF-C, required to form lymph sacs
5. LECs express proteins that lead to platelet aggregation to prevent lymphatico-venous connections
6. LECs differentiate into lymphatic capillaries and vessels


Clinical manifestations of lymphedema

-Abnormal accumulation of fluid (possibly lymph) in the interstitial spaces (often extremities)
-Abnormality in the structure or function of the lymph system
-Swollen extremities
-Phenotype is imprecise and penetrance is incomplete


Primary Lymphedema (PL)

-AD w/ reduced penetrance (80%)
-Disabling and disfiguring swelling of the limbs
-Variable expression
-Variable age of onset
-Genetic heterogeneity
-VEGFR-3 and SOX-18 mutations



Expressed in vascular endothelium - lymphatic precursor cell line
-prominent at lymphatic points of origin
-VEGFR3 KO mice showed enlarged pericardial lymphocytes, enlarged paws
-Causes is PL



-Lymphedema, predominantly of lower limbs
-onset around puberty
-Distichiasis (double row of eyelashes)
-Varicose veins
-Cleft lip/palate (4%)
-Congenital heart defect (7%)
-FOXC2 mutations