Inheritance and Risk of Genetic Disorders

Everything my GC school profs may want me to know about specific genetic disorders

Cystic Fibrosis

• mendellian, autosomal recessive

• pleiotropy → a single gene mutation affects mucus glands throughout the body, caysung seemingly unrelated effects

• Allelic Heterogeneity → multiple different mutations of the same gene will produce the same condition

Sickle Cell

• Mendelian - autosomal recessive

• only one specific mutation of a single gene causes the characteristic mishapen red blood cells, and the resulting lower blood supply + oxygen transport

• heterozygous advantage → heterozygotes often have less severe manifestations, and carry some malaria resistance, so the disorder has become more promenant in people with ancestry from high malaria risk places, like Africa

Hemophilia

• x linked recessive

• Can cause severe bruising and bleeding 

• Locus heterogeneity → multiple single gene forms-two people with the same diagnosis could have mutations at two entirely different genes

• Allelic Heterogeneity→ multiple different mutations of the same gene will produce the same condition

Polydactyly

• autosomal dominate

• variable expressivity - a characteristic extra digit can appear on only one hand, both hands, a hand and a foot, etc.

• incomplete penetrance → can appear to skip a generation despite not being recessive

• Locus heterogeneity → multiple single gene forms-two people with the same diagnosis could have mutations at two entirely different genes

Duchenne Muscular Dystrophy

• x linked recessive and fatal - mostly males experiencing selective pressure

• 10% of isolated cases are due to maternal germ line mosaicism, and 1/3 from de novo mutations

• causes progresive muscle weakness

• Caused by a premature stop codon that creates transcription factors for miRNA’s that silence the dystrophin gene, and promote inflammatory cytokines to break down the muscle

• Exon skipping therapy → makes the mutation in-frame, removes the premature stop codon, and reduces severity

Marfan Syndrome

• autosomal dominate

• connective tissue disorder

Tay Sachs

• autosomal recessive

• lysosomal storage disorder → b-HEXA enzyme is unable to break down GM2 sphingolipid

• progressive muscle weakness, neurodegeneration, cherry red spots on eyes

• Founder Effect → highly prominent among Akazaki jews in North America, due to a migration skewing the allele frequency among their population

• NOT included in newborn screening because only effective treatment is enzyme replacement therapy 

• Pseudodefficiency alleles make sequencing a necessary part of diagnosis 

Rhett’s Disease

• x linked dominate

• Neurodevelopmental disorder

• Lethal in males → thus 99% of cases are from de novo mutations

Achondroplasia

• Autosomal dominate

• most common cause of severe short stature, due to an underdeveloped skeletal system

• 7/8 cases are de novo mutations

• BUT mating within the “dwarf” community has increased the prevalence of the fatal homozygous genotype, due to nonrandom mating

Fragile X

• x-linked trinucleotide repeat expansion

• Expansions typically onl;y happen in maternal line

• Most common single-gene cause of inherited intellectual disability and autism

• Comes with distinctive physical features-long face w/ broad forehead, large low-set ears,, etc.

• Large range of expansions that are not fully diseased, but carry premiutations that could cause neurodegeneration/ataxia in males (FXTAS) or ovarian insufficiency in females (FXPOI)

Huntington’s Disease

• fatal neurodegenerative disorder

• Polyglutamine (CAG repeat on a coding exon region) trinucleotide repeat expansion

• Largely dominate inheritance pattern with complete penetrance, and expansions only happening in the paternal line

• Longer trinucleotide expansions lead to earlier age of onset and more severe presentation

MELAS

• Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like episodes

• Disorder stemming from Mitochondrial DNA - can only be maternally inherited

• Common features - recurring stroke episodes, seizures, migranes, and/or dementia from an early age (<40).

MERRF

• Myoclonic Epilepsy with Ragged Red Fibers

• Disorder stemming from Mitochondrial DNA - can only be maternally inherited

• Common features- ataxia (uncoordinated, uncontrolled muscle movements), seizures (epilepsy), irregularly-shaped red muscle fibers

Albinism

• * Autosomal Recessive

• Light pigmentation and poor eyesight

Neurofibromatosis

• Autosomal Dominate

• Cafe-au-lait spots, neurofibroma or and/or optic glioma tumors → variable expressivity

PKU

• Disruption of PAH enzyme, which converts the → tyr,  or its cofactor BH4

• Aminoacidopathy → buildup of toxic amino acid (phe) and decrease in an amino acid usually not found in diet (tyr)

• Intellectual and behavioral differences, seizures/parkinson’s-like features, decreased pigmntation (Tyr is involved in melanin production)

• Detectd in newborn screening, followed by sequencing the PAH gene or looking at Phe:Tyr ratio in plasma amino acids

• Treated withspecialized diet, palynziq enzyme substitution, 

Galactosemia

• Disruption of GALT enzyme in glucose metabolism

• Buildup of toxic Gal-1-p

• Detected in newborn screening followed by GALT enzyme (low) or galactose (high) analysis

• Dietary intervention must be started within a few days of birth

OTC Deficiency

• Only x-linked urea cycle disorder

• Ammonia accumulation

• Problems revolving around feeding struggles (vomiting, lethargylow body temp)

• Can be treated by cleaning ammonia out of the blood w/ dialysis, liver transplant, or nitrogen scavenger drugs (Ammonul) that push the excess ammonia into being used in secondary pathways

Gaucher Disease

• Lysosomal storage disorder affecting breakdown of toxic glucocerebroside (GL-1)

• NOT in most newborn screens

• Symptoms include enlarged spleen/liver, bone pain and deformaties, cytopenias (blood cell deficiencies)

• Detected by testing GBA enzyme (low) or b-glucocerebroside (high)  activity

• Treatment → cerezyme enzyme replacement therapy

Alkaptonuria

• Aminoacidopathy → HGD enzyme cannot breakdown homogenistic acid as part of Tyr degredation pathway

• HGA forms cartilage-binding pigments in urine and connective tissue tissue → dark colorations

• NOT in newborn screening → detected using urine samples

MPS1

• lysosomal storage disorder → disruption of IDUA enzyme, and resulting accumulation of GAG’s, increases size of lysosome

• multisystemic → symptoms include ID, flat/wide facial features, corneal clouding, macrocephaly/hepatosplenomegaly

• Detectd in newborn screening followed by gene sequencing or IDUA (low)/GAG (high) activity

• Treatments include bone marrow transplants to introduce more healthy stem cells, or aldurazyme enzyme replacement therapy

Biotinidase Deficiency

• due to defective recycling of biotinidase, which is important for carboxylase enzyme function

• often associated with alopecia, low muscle tone (hypotonia), ataxia, hearing and vision problems

• Detected by newborn screening/sequencing followed by BTD enzyme measurment (low)

cystinuria

• transport defect → a transporter protein in kidneys causes amino acids to not be reabsorbed from urine

• concentration of amino acids created crystals that can cause UTI ‘s and kidney/bladder stones

• Detected via urine sample

Homocystinuria

• defect in CBS enzyme prevents breakdown of methionine to cystine

• potential for CNS problems (ID, seizures) and marfan habitus (tall and slender features)

• Detected via newborn screening followed by checking plasma amino acids for increased meth and homocysteine

• supplementation with either vitamin B6 or B12 + folate, or promoting alternate methylation with betain therapy, will reduce homocystine levels by turning them back to methionine, but will not lower elevated methionine levels

Carnatine deficiency

• Transport defect → disruption of OCTN2 gene means carnitine proteins will not be brought into cells to transport fatty acids into the mitochondria for metabolism, or remove toxic free carbon chains

• often associated with myopathy (muscle weakness)

• detected in newborn screening followed by reduced carnatine and acylcarnatine profiles

familial hypercholesterolemia

• receptor defect → either prevents the LDL receptor itself from working, prevents it from recycling itself and popping back out of the cell’s surface after sinking down with an LDL, or be a defect in toe APOB protein needed for LDL’s to bind to the receptor

• LDL’s are sticky → if not taken up and processed by cells, can build up under artery walls and crate blockages → heart disease

• Statin drugs can block cholesterol synthesis, Ezetimibe decreases absorption of cholesterol from food, bile acid sequesterants simulate liver to use excessive cholesterol to make bile → all limit the body’s cholesterol supply to what’s already in the blood

Fabray

• only x-linked lysosomal storage disorder → defect in GLA enzyme causes increase in GL3 sphingolipids

• major symptoms → heat intolerance from an inability to sweat, and prickling/burning sensation in the hands and feet, and increased risk for kidney/heart disease

• Treatments include fabrazyme enzyme replacement, or sometimes a kidney transplant

Prader-Willi

• Imprinting disorder → missing expression from a gene only active on paternal chromosome 15, either through mutation or uniparental disomy

• Major symptom is compulsive eating/obesity

Angelmann

• imprinting disorder → missing expression of a gene oinly active on maternal chromosome 15, either due to mutation or uniparental disomy

• major symptom → frequent happy/excitable demeanor

Spinal Muscular Atrophy

• Caused by missing SN1 gene

• First personalized RNA therapy treatment → prevents truncation of SN2 protein via alternate splicing so it can compensate for the missing SN!

Hutchinson-Gilford Progeria syndrome

• Premature aging disorder resulting from a defect in alternative splicing