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113 Cards in this Set
- Front
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Kearns-Sayre Syndrome (KSS)
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Mitochondrial deletion phenotype
Onset before age 20 (usually childhood) Pigmentary retinopathy ("salt and pepper" rod/cone dystrophy) Progressive external opthalmoplegia (PEO) In addition, at MUST have at least one of: Cerebellar ataxiaCardiac conduction block Cerebrospinal fluid protein >100 mg/dL, Ragged-red fibers on muscle biopsy Lactic acidosis Decreased activity of respiratory chain complexes containing mtDNA-encoded subunits Frequent: Hearing loss Dementia Limb weakness Diabetes mellitus Hypoparathyroidism Short stature, growth hormone deficiency |
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SURF1
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NUCLEAR encoded
Recessive inheritance Component of MT Cytochrome C oxidase Deficit can cause Leigh syndrome |
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Leigh syndrome
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Mitochondrial disorder
(rarely deletions) Lesions of the basal ganglia and brain stem Brain MRI: characteristic T2-weighted hyperintense lesions |
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What are the mitochondrial deletion syndromes? (3 overlapping phenotypes)
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Kearns-Sayre Syndrome (KSS)
Pearson Syndrome Progressive External Ophthalmoplegia (PEO) Rarely: Leigh Syndrome |
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In the various mitochondrial deletion syndromes: What tissues are the deletions most abundant in?
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Usually simplex (only instance in a family)
mtDNA deletions ranging from 2-10 kilobases. 90% of individuals with KSS: Large-scale (1-10 kb) mtDNA deletion Usually present in all tissues Often undetectable in blood cells (tissue heteroplasmy) Do a muscle biopsy Pearson syndrome: mtDNA deletions most abundant in blood Progressive external opthalmoplegia (PEO) mtDNA deletions only in skeletal muscle |
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Pearson "Marrow Pancreas" syndrome
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Most severe
Mitochondrial deletion syndrome Sideroblastic anemia Exocrine pancreas dysfunction (suppl with enzymes) Usually fatal in infancy Failure to thrive, malabsorption Sideroblasts seen on bone marrow exam (Failure to form complete heme molecules--synth in mitochondria; iron buildup in mitochondria; lack of mature RBC) If survive, develop Kearns-Sayre |
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Progressive external opthalmoplegia (PEO)
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Mitochondrial deletion syndrome
Relatively benign Ptosis (drooping eyelids) Paralysis of the extraocular muscles (ophthalmoplegia), Oropharyngeal weakness Proximal limb weakness Ataxia |
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What surveillance for mitochondrial deletion disorders?
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ECG and echocardiogram every 6-12 months
Yearly hearing exam Yearly endocrinologic evaluation Agents/circumstances to avoid: Drugs potentially toxic to mitochondria (chloramphenicol, valproic acid...) |
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Recurrence risks of MT deletion syndromes?
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Very low
Mother usually unaffected (maternal inheritance of mitochondria) Sibs not at risk Father not a carrier |
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Features of metabolic conditions
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Typically appear after a period of good health
Unmasked by "stressors" Infection, fever Fasting, malnutrition Dehydration, excessive protein Trauma of birth Altered mental states Failure to thrive Regression, MR Multiple organ systems involved Can present at ANY AGE |
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Which disorders associated with SIDS?
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Disorders of fatty acid metabolism
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Hyperammonemia symptoms
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Respiratory distress
Seizures Lethary Hypotonia Hypothermia in neonate |
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What types of conditions have a high ammonia level?
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Urea cycle disorders
Organic acidemias Fatty acid oxidation defects Sepsis |
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Hypoketotic hypoglycemia
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Fatty acid oxidation disorders
Dehydrated, vomiting Low ketones |
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What if altered mental status, glucose and electrolytes are normal, but high urine ketones in newborn?
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Maple Syrup Urine Disease
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Lactic acidemia
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Mitochondrial disorders
Disorders of pyruvate metabolism Gluconeogenesis disorders Glycogen storage disorders |
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Characteristics of the MT genome
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16.5 KB, circular
2-10 copies per mitochondrion Contains 37 genes No introns 13 electron transport chain proteins 22 tRNAs 2 rRNAs |
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Maternal inheritance
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Look for pedigrees in which:
All of a sister's children are affected None of a brother's children are affected |
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Replicative segregation
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Duplicate MT DNA before cell division, then segregates to the new cells
Can influence degree of heteroplasmy |
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Bottleneck
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Primary oocyte has many mitochondria
Loses most during maturation In zygote, number of mitochondria increase again Influences heteroplasmy of cells |
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Threshold
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Proportion of mutant mtDNA must exceed threshold for disease
Threshold lower in tissues with higher energy demands: Brain Heart Muscle Kidney Endocrine system |
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High mutation rate
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MT DNA mutation rate
10-100 times nuclear DNA Replicated 1000x more Oxidative damage No histones to protect DNA Inefficient repair mechanisms |
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Heteroplasmy
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One cell can have thousands of mtDNA molecules
If mutation in one molecule, others still wild-type Heteroplasmy: co-existence of wild-type and mutant mtDNA within the same cell |
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Which complex produces ATP?
(Oxidative phosphorylation) |
Complex V
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Which complex contains only nuclear-encoded proteins?
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Complex II
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Pyruvate Dehydrogenase
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Turns pyruvate to Acetyl Co-A
At entry to the mitochondrion Sends it to TCA cycle to produce energy |
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Consequences of MT disorders
(defect in oxidative phosphyorylation) |
Dementia
Deafness Blindness Problems with eye movement Ptosis Seizures Ataxia Tremors Diabetes Cardiomyopathy Heart failure Sensory neuropathy Dystonia (muscle contractions, sustained postures or repetitive movements) |
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Location of mutations in MT disease
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MT DNA
nuclear DNA 1000 proteins in the mitochondria Only 13 produced by MT DNA MOST mitochondrial disorders due to nuclear mutations Some are X-linked Most recessive |
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Genotype-phenotype correlations
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Nuclear DNA mutations
may present in childhood mtDNA mutations tend to present in adulthood |
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mtDNA gene mutations
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Encodes 13 proteins
All 13 function in the electron transport chain: 7 in complex I (most potential for mutation) 1 in complex III 3 in complex IV 2 in complex V |
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NARP
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T8993G mutation in MT-ATP6 gene
Part of complex V (ATP synthase) Neurogenic muscle weakness, Ataxia, Retinitis Pigmentosa (blindness) Symptoms present in early childhood: Proximal muscle weakness (hypotonia) Sensory neuropathy Ataxia Retinitis pigmentosa Learning disabilities Seizures Developmental delay Failure to thrive |
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Leigh syndrome causes
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Often set off by a viral infection
Locus heterogeneity 20% MT DNA causes: T8993G mutation in MT-ATP6 gene Part of complex V (ATP synthase) MT tRNAlys mutations MT DNA deletions 35% Nuclear OXPHOS causes: Complexes I, IV 10% Pyruvate Dehydrogenase mutations OTHER |
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MELAS
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Due to mtDNA OX PHOS gene mutations
or tRNA and rRNA mutations 80% is A3243G mutation in tRNAleu Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) Symptoms present in childhood Stroke (before age 40) Seizures, migraines, dementia Retinitis pigmentosa, Hearing Loss Recurrent vomiting, anorexia Exercise intolerance, limb weakness Lactic acidosis, ragged red fibers |
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Leber hereditary optic neuropathy (LHON)
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Due to mtDNA OX PHOS gene mutations
3 common point mutations HOMOPLASMIC (in all but 10-15% cases) Visual blurring Become legally blind Some movement phenotype associated Males more affected: 50% risk (females 10% risk) Gender and age-dependent penetrance |
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T8993G mutation causes which disorders?
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Based on heteroplasmy symptoms
<60%: asymptomatic 70-90%: NARP phenotype >90%: Leigh syndrome |
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Leigh syndrome features
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Progressive, devastating Neurological disease
(many die within 5 years) Developmental delay and/or regression Failure to thrive Respiratory difficulties Hypotonia, Spasticity Ataxia, Seizures Optic atrophy, Retinitis Pigmentosa Lactate peak or lactic acidosis Bilateral degeneration of basal ganglia Hyperintense T2 signals on MRI in brain stem / basal ganglia |
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What kind of testing for NARP and Leigh syndrome?
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Point mutation and deletion panel
For the common mutations/deletions Including T8993G |
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mtDNA Mutations in tRNA/rRNA Genes
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Needed for all protein synthesis in the MT
Leads to deficient activity of all complexes except complex II, which is nuclear encoded MERFF, MELAS Leigh syndrome Diabetes Deafness Mitochondrial myopathy Cardiomyopathy (maternally inherited) |
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MERRF
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Myoclonic epilepsy with ragged red fibers
(MERRF) |
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Ragged red fibers in which syndromes?
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MERRF
MELAS Kearns-Sayer |
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Consequences of
A3243G mutation in tRNAleu |
Based on Heteroplasmy
10-30%: Diabetes II +/- deafness > 75%: MELAS |
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MT DNA deletions:
What makes them more severe? |
Generally cause severe phenotype
Probands don’t reproduce (sporadic) All involve at least one tRNA gene Deficiency of all mtDNA encoded proteins Deficient activity of complexes I, III, IV, and V Severity correlates with tissue distribution Not size or location of deletion |
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Nuclear DNA mitochondrial diseases
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THESE DON'T HAVE MATERNAL INHERITANCE
Pyruvate dehydrogenase deficiency Alpers syndrome Complex I, III, IV, and V deficiencies Coenzyme Q10 deficiency Friedreich ataxia Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) mtDNA deletion syndrome mtDNA depletion syndrome Mohr-Tranebjaerg syndrome |
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Pyruvate dehydrogenase deficiency
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Most commonly X-linked
X-LINKED Glucose to pyruvate Into the MT Pyruvate to Acetyl Co-A to energy COMPLEX of proteins Most common cause: mutations in PDHC E1 alpha gene X-linked dominant Lactic acidosis Energy deficiency |
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What is an X-linked MT disorder?
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Pyruvate dehydrogenase deficiency
(the most commonly mutated gene in the complex is X-linked dominant) |
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Symptoms of pyruvate dehydrogenase deficiency?
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Can have PRENATAL ONSET brain malformations
Hypotonia Abnormal eye movements Developmental delay Carbohydrate-induced episodic ataxia Progressive neurologic deterioration Seizures, encephalopathy Sensorineural hearing loss Cortical visual impairment Congenital lactic acidosis |
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Friedreich ataxia
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Most common form of hereditary ataxia
1/50,000 RECESSIVE FXN gene GAA triplet-repeat expansion, intron 1 (2% have an expansion in one FXN allele and an inactivating FXN mutation in the other) Spinal cord and peripheral nerves degenerate Cerebellar atrophy Ataxia, sensory deficits Dysarthria (slowness and slurring of speech) Hypertrophic cardiomyopathy Diabetes |
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Friedreich ataxia
Repeat sizes |
GAA repeats in FXN gene
BOTH MATERNAL AND PATERNAL EXPANSION 5-33 Normal 34-65 Premutation (44-66 Borderline, reduced penetrance) 66-1700 Full Mutation (GAGGAA)n sequence interruptions may stabilize |
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Alpers syndrome
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POLG mutations
Autosomal recessive One of most severe POLG disorders mtDNA depletion Severe encephalopathy Intractable seizures Brain imaging abnormalities Liver failure |
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Adult onset Tay-Sachs
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More variable neurologic findings:
Bipolar form of psychosis Progressive dystonia, Spinocerebellar degeneration, Motor neuron disease The juvenile (subacute), chronic, and adult-onset variants of hexosaminidase A deficiency have: Later onsets, Slower progression |
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Rare dominant MT disorder
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Progressive external opthalmoplegia
Autosomal dominant form POLG mutation |
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Lesch-Nyhan disease
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Low Hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme activity
HPRT sequence analysis X-linked recessive Hyperuricemia (high uric acid) Kidney stones as a result Hypotonia, dev delay (visible 3-6 months) Motor dysfunction Resembles cerebral palsy Cognitive, behavior problems PERSISTENT SELF-INJURIOUS BEHAVIOR Gout in some female carriers |
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Which fatty acid oxidation disorder can have significant ketosis?
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SCAD
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Is liver failure a characteristic of organic acidemias?
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No
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Acute Intermittent Porphyria
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Hydroxymethylbilane synthase
(HMBS) deficiency Disorders of heme synthesis Red-brown urine during attacks Autosomal dominant Reduced penetrance (10-50%) Visceral, peripheral, autonomic, CNS Abdominal pain (initial sign of attack) Nausea, vomiting, constipation or diarrhea, abdominal distention, urinary retention, incontinence Peripheral neuropathy Weakness in arms or legs Permanent quadriplegia may occur Psychiatric: insomnia, agitation, hysteria, anxiety, apathy or depression, phobias, psychosis, organic disorders, delirium, somnolence, or coma. |
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Homocystinuria
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Cystathionine Beta-Synthase
(CBS) Deficiency Autosomal recessive Marfan-like [BUT NO JOINT LAXITY] Homocystinuria caused by cystathionine β-synthase (CBS) Developmental delay/MR Ectopia lentis and/or severe myopia Skeletal abnormalities (excessive height and limb length) Arachnodactyly Thromboembolism B6-responsive milder than non-responsive Ectopia lentis by age 8 Tall, slender (‘marfanoid’) habitus Osteoporosis Thromboembolism major cause of early death and morbidity IQ ranges widely, from 10 to 138 Mean IQ 79 vs 57 for those who are B6 non-responsive. Seizures, psychiatric problems |
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Serum signs of X-linked ALD
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ABCD1 gene
Testing clinically available X-linked MRI abnormal in males with neurologic symptoms High plasma concentration of very long chain fatty acids (VLCFA) |
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Which type of disorder is NOT tested for my MS/MS (tandem mass spec) on newborn screening?
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Lysosomal storage diseases
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Untreated Galactosemia
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Erythrocyte galactose-1-phosphate uridyltransferase
(GALT) enzyme deficiency Autosomal recessive Glucose plus galactose = lactose PREMATURE OVARIAN FAILURE Cataracts Sepsis (E. coli infections) Feeding problems, failure to thrive Liver failure Bleeding Neonatal death MR If lactose/galactose-restricted diet is provided during the first ten days of life, reverses Risks remain once treated: Developmental delays Speech problems (termed "verbal dyspraxia") Abnormal motor function Females at risk for premature ovarian failure |
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Which urea cycle disorder has risk for progressive liver disease?
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Argininosuccinic acid LYASE deficiency
ASL gene Autosomal recessive Hepatitis, cirrhosis Coarse brittle hair that breaks easily |
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Which urea cycle disorder has the mildest ammonia crises?
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Arginase deficiency (last step of cycle)
Neonatal and early childhood may be normal |
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Rickets
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Calcium
Phosphate or Vitamin D deficiency |
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Renal Fanconi Syndrome
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Kidneys fail to reabsorb small molecules:
Happens with metabolic liver disease?? Urinary loss of electrolytes (sodium, potassium, bicarbonate) minerals, glucose, amino acids, and water Results: Polyuria (excessive urination) Polydipsia (excessive intake of fluid) Dehydration Hypophosphatemic rickets (due to loss of phosphate) Growth retardation |
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Fatty acid oxidation disorders
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Hypoketotic hypoglycemia
Lethargy Seizures Coma Triggered by a common illness; Hepatomegaly and acute liver disease Sudden unexplained death |
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Menkes disease
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Mutations in copper-transporting ATPase gene (low serum copper; low absorption from intestine)
(ATP7A gene) X-linked Neurodevelopmental syndrome At 2-3 months: Loss of developmental milestones Hypotonia, seizures Failure to thrive Characteristic changes in hair: (short, sparse, coarse, twisted, and often lightly pigmented). Temperature instability Hypoglycemia Death by age three |
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Wilson disease
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Autosomal Recessive
Too much copper ATP7B gene Hepatic, neurologic, or psychiatric disturbances Range of ages: 3-50 Liver disease: Recurrent jaundice Acute hepatitis-like illness, Chronic liver disease, liver failure Neurologic: Movement disorders (tremors, poor coordination, loss of fine-motor control, chorea, choreoathetosis) or Rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement). Psychiatric: Depression, neurotic behaviors, disorganization of personality, intellectual deterioration |
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Zellweger syndrome and its partners
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PEX1
Plus 12 other peroxin genes Required for peroxisome assembly Part of the membrane Peroxisome biogenesis disorder High plasma very-long-chain fatty acids (VLCFA, in range 24-26) (Branched) Continuum: Zellweger syndrome (ZS), most severe Neonatal adrenoleukodystrophy (NALD) Infantile Refsum disease (IRD), least severe |
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Zellweger syndrome
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Neonatal presentation
Large anterior fontanelle Profound hypotonia Characteristic facies Seizures Inability to feed Liver cysts Hepatic dysfunction Chondrodysplasia punctata (bony stippling of kneecaps and long bones) Significantly impaired Usually die during the first year Apnea or infections/respiratory compromise |
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Autism is associated with which conditions?
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1-3% autistic kids have Fragile X
FMR1 gene (50% Fragile X show autism) Macrocephaly plus autism PTEN gene Sotos syndrome NSD1 Lack of awareness of social cues Rett syndrome MECP2 1% Tuberous Sclerosis Complex TSC1/2 1-3% Neurofibromatosis 1 NF1 gene Angelman syndrome Duplication of 15q11-q13 Down syndrome San Filippo syndrome Phenylketonuria Smith-Magenis syndrome 22q13 deletion Smith-Lemli-Opitz syndrome |
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The MPS subtypes
(mucopolysaccharidoses) |
MPS I Hurler/Scheie
MPS II Pompe MPS III Sanfilippo MPS IV Morquio |
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MPS III Sanfilippo
PROTOTYPICAL LYSOSOMAL STORAGE DISORDER Lysosomal accumulation of GAGs |
Most common of the MPSs
4 different enzyme defects can cause it 1/70,000 CAN BE TAKEN AS AUTISM Hyperactive, aggressive, destructive, deterioration in speech CNS disease predominates Less skeletal and soft tissue involvement than other MPSs Can't break down heparan sulfate Declining learning ability ages 2-6 |
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MPS I Hurler/Scheie
glycosaminoglycans (GAG) accumulation |
Autosomal recessive
Bone marrow transplant helps Coarse facial features Hepatosplenomegaly Skeletal deformities Corneal clouding Severe form: Infants appear normal at birth Umbilical or inguinal hernia Upper respiratory-tract infections <1 year Coarsening facial features Gibbus deformity of the lower spine Progressive skeletal dysplasia (dysostosis multiplex) involving all bones Linear growth ceases by age 3 Intellectual disability progressive, profound Hearing loss common Death by cardiorespiratory failure <10 years Less severe forms, cardiac valve disease, joint problems, may not have MR, hearing loss, learning disabilities |
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MPS II Hunter
glycosaminoglycans (GAG) accumulation |
Mostly affected MALES
X-linked Enzyme therapy; not cross BBB Severity ranges widely Cognitive deterioration Progressive airway disease Cardiac disease Macrocephaly Macroglossia Hoarse voice Conductive and Sensorineural hearing loss Hepatomegaly and/or splenomegaly Dysostosis multiplex Joint contractures (including TMJ) Spinal stenosis Carpal tunnel syndrome |
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Diabetes facts
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Type I associated with HLA locus
Type II greater heritability MODY (rare) is autosomal dominant |
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POLG disorders
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Catalytic subunit of MT DNA polymerase (Twinkle is the helicase)
Autosomal recessive, nuclear Can cause encephalopathy Epilepsy Liver Failure Myopathy MR Hearing loss Ataxia Progressive external opthalmoplegia Only one type of mutation autosomal dominant: Progressive external opthalmoplegia |
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What disorder has scent of sweaty feet?
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Isovaleric acidemia
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Hunter or Hurler benefit from bone marrow transplant?
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Hurler
Also, no evidence helps in San Filippo |
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Fabry enzyme
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Lysosomal
α-galactosidase (α-Gal A) |
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CONSIDER NONPATERNITY
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...as an explanation
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PKU
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Lighter hair
Lighter pigment If left untreated MR Slower attention and focus |
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MT DNA depletion syndromes or multiple DNA deletions
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Have to do with copying of the MT DNA, which is done by NUCLEAR genes.
Most likely recessive inheritance. |
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Chief lysosomal storage disorders
(Acid recycling compartments of the cell) |
Gaucher
MPS disorders (Hunter, Hurler) Krabbe disease (on newborn screening) Pompe Fabry (X-linked) Tay-Sachs |
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X-linked lysosomal storage disorders
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Fabry
Danon (Lamp-2) Hunter (MPS type II) Others are autosomal recessive |
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Incidence of lysosomal storage disorders
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>40 disorders
Together, overall incidence: 1/10,000 Some as rare as 1/million |
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Genetics of Pompe disease
Lysosomal storage disorder AND Glycogen storage disease (some glycogen breakdown takes place in the lysosome) |
Glycogen storage disease Type II
1/40,000 African Americans: Infantile onset 1/14,000 Autosomal recessive Liver, heart, muscle Acid alpha glucosidase "acid maltase" GAA gene 3 common mutations for China/Taiwan, African descent, and late-onset cases Enzyme activity in fibroblasts Treatment: ERT Cardiac and skeletal muscles |
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I-cell and Nieman Pick Type C
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Deficient trafficking of enzymes to the lysosome
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Characteristics of Pompe disease
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Infantile onset: <12 months
Floppy, hypotonia, no head control Enlarged tongue, lax face Huge hearts on X-ray--HCM Leads to cardiac failure Respiratory insufficiency Respiratory infections, aspiration pneumonia Late onset: Progressive muscle weakness, Proximal: trunk, lower limbs Gait abnormality Respiratory insufficiency Daytime headache, somnolence Scapular winging Gower's sign Fibromyalgia NO CARDIAC DISEASE |
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Krabbe disease
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Nervous system
(Globoid cell leukodystrophy) Galactocerebrosidase (GALC) enzyme activity Muslim communities in Jerusalem Progressive neurodegeneration Toxic intermediate destroys myelin sheaths Death before age 2 Spasticity Irritability Loss of milestones Blindness Deafness Bone marrow transplant can preserve cognitive function Still gross motor delays Late-onset: Progressive weakness Blindness Mental deterioration |
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Fabry disease
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Vascular Endothelial Cells
X-linked Alpha-galactosidase A enzyme GLA gene 1/40,000 males NO COMMON MUTATIONS LVH, arrhythmias, stroke Renal deterioration Pain crises in hands and feet Hypohidrosis GI distress and dismotility Corneal clouding Angiokeratomas on skin GL3 ceramide accumulation |
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Danon disease
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X-linked
LAMP2 mutations lysosomal associated membrane protein-2 Severe early-onset HCM in males Skeletal myopathy Retinal dystrophy Carrier females show cardiac phenotype |
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Gaucher disease
Most common lysosomal storage disorder |
Macrophages involved
GBA gene Glucosylceramidase 1/50,000 1/900 AJ 4 mutations in 90% of AJ cases Enzyme deficiency testing gold standard Hepatosplenomegaly Bone disease (crumbling hip socket) Neurologic disease for Types 2 and 3 only 6x risk for multiple myeloma |
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MPS diseases
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Common symptoms:
Seizures, behavior problems, sleep disturbance, MR Corneal clouding, retinal dystrophy Sensorineural hearing loss Frequent respiratory infections Cardiomyopathy Degenerative hip dysplasia, kyphoscoliosis Hepatosplenomegaly UMBILICAL AND INGUINAL HERNIA |
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Does enzyme replacement therapy cross the BBB?
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No--so more concerned if there is a CNS component to the disease
Lysosomal membranes have mannose-6-phosphate receptors Used to target enzymes to the lysosome |
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Which lysosomal storage diseases currently have enzyme replacement therapy options?
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Gaucher
Fabry Pompe MPS I (Hurler) MPS II (Hunter) MPS VI |
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Which lysosomal storage diseases currently use bone marrow transplant?
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MPS I (Hurler)
MPS VI X-ALD [peroxisomal] Krabbe disease Done to stop neurological progression |
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Mucopolysaccharidoses
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All recessive
Except Hunter (MPS II)-X-linked recessive 1/22,000 overall incidence GAGs accumulate A component of Cornea Cartilage Bone Connective tissue CNS |
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Dysostosis multiplex
(seen in many MPSs) |
Collection of skeletal malformations
Thickened calvarium Abnormal spacing of teeth Abnormally shaped vertebrae Ribs and epiphyses abnormally shaped Dysplastic pelvis |
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Criteria for newborn screening
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Started in 1960 with PKU
Identify treatable life-threatening diseases before presentation -Identifiable biochemically before clinically obvious -Inexpensive test that works in dried blood dpots -Incidence high enough (1/15,000-1/60,000) -Demonstrated benefit to early intervention |
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Tay Sachs genetics
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Hexosaminidase A deficiency
HEXA gene Autosomal recessive 1/30 carrier frequency AJ (1/3600 AJ prevalence) 2 null mutations account for 94% of disease French Canadian Cajun Old Order Amish 1/300 carrier frequency in general pop 1/300,000 prevalence in general population 35% of non-Jewish have a pseudodeficiency allele (one of 2) |
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Hunter and Hurler--which GAGs?
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BOTH
have dermatan, heparan Need enzyme testing to distinguish between them |
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MPS I
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Hurler, Hurler-Sheie, Scheie
1/100,000 Die in first decade Corneal clouding Glaucoma SN deafness Cardiomyopathy Valve lesions Hepatosplenomegaly Hernias Hydrocephalus Seizures Behavior issues Sleep disturbance MR Carpal tunnel syndrome Kyphosis-scoliosis Degenerative hip dysplasia Progressive airway disease Cognitive deterioration Enzyme replacement therapy and BMT available |
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MPS III
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Sanfilippo
No treatment Die in teens Heparan 4 enzymes involved Corneal clouding Swallowing issues Diarrhea, drooling Hydrocephalus, seizures Sleep disturbance Behavior issues MR Degenerative hip dysplasia Deafness, blindness progressive |
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MPS IV
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Morquio
Seems least severe Die at 20s-30s Corneal clouding Degenerative hip dysplasia Kyphosis-scoliosis NO CNS INVOLVEMENT |
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Isovaleric Acidemia
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Organic acidemia
Isovaleryl CoA dehydrogenase deficiency IVD gene Leucine break-down pathway THE STEP FOLLOWING MAPLE SYRUP URINE DISEASE Hi C-5 acylcarnitine (isovaleryl) Is a common mild mutation found only on NBS "Sweaty feet" odor Hi ammonia, lactate, ketones Tachypnea Lethargy Vomiting Seizures Coma Tx: Protein restriction, carnitine |
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Maples Syrup Urine Disease (MSUD)
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"A maple tree has branches"
1/185,000 1/200 Mennonites Organic acidemia Branched-chain alpha-ketoacid dehydrogenase deficiency BCKAD gene Valine, Leucine, Isoleucine break-down pathway THE STEP BEFORE ISOVALERIC ACIDEMIA Plasma amino acids: Hi branched chain Urine organic acids: Hi branched chain "Sweet" odor Irritability, poor feeding, lethargy Hi ketones Encephalopathy 4-5 days Coma 7-10 days Mild-moderate MR ADHD 6-12 years Anxiety/depression Pancreatitis Tx: Protein restriction, carnitine LIVER TRANSPLANT |
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Phenylketonuria (PKU)
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Organic acidemia
Phenylalanine hydroxylase deficiency Turns Phe into Tyrosine PAH gene HI PHENYLALANINE >1000 uM 1/10,000 Carrier rate: 1/50 Hi Phenylalanine Lo Tyrosine Pale dry skin Blond hair, blue eyes MOUSY odor Seizures Behavior problems Abnormal gait Osteopenia Profound MR if untreated |
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Maternal PKU
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Teratogenic
Congenital heart defects IUGR Microcephaly MR Lo Phe diet |
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Tyrosinemia Type I
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Fumarylacetoacetate hydrolase deficiency
FAH gene 1/100,000 (higher French Canadian) Acute liver failure Cirrhosis HEPATOCELLULAR CARCINOMA Renal failure Enlarged kidneys HCM Pancreatic islet cell hypertrophy Weakness Episodic paralysis, peripheral neuropathy CABBAGE ODOR (French eat cabbage gratin) Hi Tyrosine, Phenylalanine, Methonine Same pathway as PKU (further down) Lo-protein diet |
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Propionic Acidemia
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VOMIT breakdown
Deficiency of Propionyl-CoA Carboxylase PCCA and PCCB (2 subunits) End of valine breakdown pathway started by PKU 1/100,000 Higher in Amish and Mennonites BIOTIN DEPENDENT carboxylase Mitochondrial enzyme |
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What are the VOMIT precursors?
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PCC (Propionyl Co-A Carboxylase)
Needed to break them down Propionic Acidemia the result otherwise Valine Odd-chain fatty acids Methionine Isoleucine Threonine Elevated C3 on acylcarnitine Lactic acid, hi ammonia, ketosis, hypoglycemia Pancytopenia Hi glycine Poor feeding, vomiting, dehydration Hypotonia, seizures, lethargy Hyperammonemia Infection Cardiomyopathy Pancreatitis Basal Ganglia Stroke Lo protein diet, carnitine |
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Holocarboxylase Synthetase Deficiency
(early onset) |
Multiple carboxylase deficiency
Needed to add biotin to 4 carboxylases Like the one not working in Propionic Acidemia (mitochondria) Or Pyruvate carboxylase (on way into mitochondria) Feeding, breathing problems Hypotonia Lethargy Seizures Rash/Alopecia Acidosis, high ammonia Treatment: Biotin, Carnitine |
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Biotinidase deficiency
(late onset) |
Disorder of biotin recycling
1/60,000 Carrier freq: 1/120 Seizures Hypotonia Ataxia Dev delay Vision and hearing loss Alopecia Skin rash Treatment: Biotin (B-vitamin) |
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Medium chain acyl-coenzyme A dehydrogenase deficiency
(MCADD) |
ACADM gene
One common Caucasian mutation Beta-oxidation of 4-12 carbon chains 1/15,000 1/70 Caucasians are carriers Acylcarnitine: Elevated C6, C8, C10 Precipitated by illness, fasting... Hypoketotic hypoglycemia (NO KETONES) Vomiting, lethargy Seizures Hepatomegaly Acute liver failure Sudden death Avoid hypoglycemia IV fluids and glucose when sick Carnitine supplementation Low fat diet |
