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Info


A. Overview of Human Genome [1,2,3]

  1. Consists 23 chromosomes (chrom) and ~3 billion base pairs
  2. Current estimates ~20-30,000 genes
  3. Over 4 million single nucleotide polymorphisms (SNPs) have been identified
    1. Most SNPs are considered DNA variants
    2. Some SNPs are truly mutations, that is, variants which clearly cause disease
    3. Combinations of DNA variants on different genes likely cause polygenic disease
  4. Number of different proteins coded by genes is >100,000 due to splice variants
  5. Classical genetic diseases are usually monogenic disorders (single gene mutations)
  6. Monogenic disorders usually divided into sex chrom and autosome abnormalities
  7. Smoking increases risk of chromsomal abnormalities in amniocytes from fetus [8]

B. Sex Chromosome Abnormalities [4]

  1. Relatively Common Anomalies (see below)
    1. Turner Syndrome (45,X)
    2. Klinefelter Syndrome (47,XXY)
  2. Pseudohermaphrodite
  3. Hermaphrodite
    1. Ova-testes
    2. Ambiguous genitalia
  4. Conjoined Twins
  5. Lyonization
    1. Random inactivation of an X chrom
    2. Occurs days 16-19 of embryogenesis, during morula and blastula stages
  6. Pure Gonadal Dysgenesis
    1. Pure gonadal dysgenesis with bilateral streak gonads that fail to differentiate
    2. Due to abnormalities in homeobox gene SOX9 or SRY genes on Y chrom
  7. Chrom abnormalities (sex and autosomal) may now be detected in utero
    1. Aminiocentesis
    2. Umbilical vein sampling

C. Fragile X Syndrome [5]

  1. Common cause (1:4000 males, 1:6000 females) of mental retardation
  2. X-linked dominant inheritance with incomplete penetrance
  3. Penetrance is ~80% in males, 30% in females
  4. Pathogenesis
    1. Due to expansion mutation in FMR1 gene on X chromosome
    2. Chromosomally unstable CGG repeat within gene with hypermethylation
    3. Fragile X chrom Site at Xq27.3 (near end of long arm)
    4. Carriers have >200 CGG repeats
    5. Premutation carriers have 50-200 CGG repeats
    6. Penetrance correlates only modestly with number of repeats
  5. Appearance
    1. Elongated face, prominent jaw, large ears, macro-orchidism
    2. Variety of behavioral anomalies and cognitive deficits including mental retardation
    3. Premutation carriers may have premature ovarian failure (~20%) and tremor/ataxia
    4. Females generally present with milder symptoms
  6. Polymerase chain reaction (PCR) analysis now available for diagnosis
  7. Supportive measures with anxiety reduction, schooling, behavioral modification
  8. Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) [5]
    1. Affects ~30% of FMR1 premutation carrier men between 50-60 years old
    2. Neurodegenerative disorder with progressive intention tremor and cerebellar ataxia
    3. Women may present with premature ovarian failure
    4. Diagnosis as for fragile X syndrome

D. Cerebral X-Linked Adrenoleukodystrophy (X-ALD) [7]

  1. Progressive neurodegenerative disorder
  2. CNS demyelination and adrenal cortical destruction
  3. Associated with defective ß-oxidation of very long chain fatty acids
    1. Defect in peroxisomal fatty acid degradation
    2. Gene mapped to chromosome Xq28
    3. Over 500 mutations in ALDP gene (peroxisomal membrane protein) causing X-ALD found
    4. ALDP is member of ATP binding casesette (ABC) transporters
  4. Leads to accumulation of very long chain fatty acids (VLCFA)
    1. These fatty acids accumulate in the brain, plasma and adrenal cortex
    2. Adrenal insufficiency and progressive neurodegeneration in boys
  5. Phenotypes
    1. Most patients have inflammatory demyelination in cerebral hemispheres
    2. Noninflammatory distal axonopathy (adrenomyeloneuropathy, AMN) found in ~35%
    3. About 20% of patients with pure AMN develop inflammatory cerebral involvement
    4. Often misdiagnosed as attention deficit hyperactivity disorder in male children
    5. May be misdiatnosed as multiple sclerosis in adults
  6. Diagnosis by measuring plasma VLCFA levels
  7. Brain MRI can show characteristic (but not completely specific) changes
  8. Treatment
    1. Mainly improve prognosis when offered at early stage of illness
    2. Adrenal replacement therapy
    3. Low fat diet with lipid supplements ("Lorenzo's Oil") to normalize VLCFA
    4. Hemopoietic Stem Cell Transplantation
  9. Lorenzo's Oil
    1. Mixture (4:1) glyceryl-tiolaeate and glyceryl trierucate
    2. Normalizes VLCFA levels within 4 weeks
    3. Does not appear to alter progression after onset of cerebral disease
    4. Does appear to reduce risk of developing cerebral disease
    5. Should be combined with adrenal replacement therapy
  10. Allogeneic Bone Marrow Transplantation (BMT) [34]
    1. Bone marrow cells from donor could cross into brain and slow demyelination
    2. Short and long term benefits of BMT have now been demonstrated
    3. Recommended strongly for patients with mild disease and limited MRI abnormalities
    4. Unclear if benefits pure AMN form

E. Klinefelter Syndrome [6]

  1. Most common sex chromosome disorder
  2. Occurs in ~1:500 males with substantial variation in clinical presentation
  3. Karyotype 47 XXY
    1. About 50% of cases of paternal origin (contributing XY from sperm)
    2. Some cases are a mosaic including XXY
    3. Maternal origin cases caused by an error in meiosis I or II
    4. Paternal origin only due to error in meiosis I
  4. Most common genetic cause of mail infertility
  5. Typical Appearance
    1. Gynecomastia
    2. Small testes
    3. Sparse body hair
    4. Tallness
    5. Infertility
    6. Normal arm spans
  6. Infertility
    1. Male hypogonadism
    2. Androgen deficiency
    3. Impaired spermatogenesis
    4. Leydig Cell Hyperplasia
  7. Diagnosis
    1. Usually small testes are noted
    2. Increased FSH and/or LH, with low testosterone
    3. Karyotyping is confirmatory and definitive
    4. Early diagnosis is important to prevent long term problems, improve quality of life
    5. Hormonal treatment is extremely effective in preventing morbidity
    6. Up to 65% of cases remain undiagnosed
  8. Endocrine Findings
    1. Elevated FSH >10 IU/L
    2. Elevated LH >7.5 IU/L
    3. Reduced testosterone ~7-18 nmol/L (may be in low normal range >12 nmol/L)
  9. Treatment
    1. Testosterone replacement therapy
    2. Reduces progression of osteoporosis and other morbidities
    3. Does not affect fertility
    4. Usually initiate therapy at age 11-12, around puberty
    5. Initial doses 50-100mg q2-4 weeks with testosterone ester, intramuscular
    6. Adult dose, required for life, is 200mg q2 weeks
  10. Spermatozoa from Klinefelter's patients have high frequency of chromosomal anomalies

F. Turner Syndrome [30,33]

  1. Occurs in ~1 in 2750 live-born girls
    1. 99% of Turner's Syndrome are miscarried in 1st or 2nd trimester
    2. Remainder are born full term
    3. Overall reduced life expectancy from cardiovascular or diabetic complications
  2. Due to single copy of all or part of X chrom
    1. ~50% have monosomy X (45,X)
    2. 5-10% have duplication (isochromosome) of long arm of one X chrom (46,X,i(Xq))
    3. Most of the remainder have mosaic chrom set (45,X/46,XX) with at least one additional cell lineage
  3. Single copies of specific genes linked to clinical characteristics
    1. Short stature likely due to short-stature homeobox (SHOX) gene on Xp22.33
    2. ZFX gene on Xp11.1-p22 also linked to stature
    3. USP9X (DFRX) and other genes linked to gonadal dysgenesis
    4. Gonadal failure linked to DIAPHw on Xp
    5. No clear link to soft tissue and visceral characteristics
  4. Clinical Characteristics
    1. Short stature
    2. Congenital lymphedema
    3. Gonadal dysgenesis
    4. Blunted secondary sex characteristics with abnormal ovaries
    5. Webbed neck
    6. Increase in arm carrying angle
    7. Congenital heart failure can occur
    8. Coarctation of aorta
    9. Renal abnormalities
    10. Hypothyroidism in 15-30% of cases
  5. Normal mental function except some spatial processing problems
  6. Normal external genitalia
  7. Diagnosis by karyotyping (may require molecular analysis)
  8. Treatment
    1. Exercise is critical for bone and muscle development
    2. Ovarian function: estrogen/progesterone replacement
    3. Bone stimulation: calcium and vitamin D
    4. Short stature: growth hormone ± oxandrolone
    5. Replacement therapy for hypothyroidism
    6. Monitor for insulin resistant syndromes and treat accordingly

AUTOSOMAL ABNORMALITIES

A. Marfan Syndrome
  1. Autosomal dominant
    1. Fibrillin gene abnormalities
    2. Procollagen type I gene anomalies
  2. Ectasia (dilation) of aorta
  3. Ophthalmologic abnormalities - lens dislocations most common
  4. Elongated fingers, large hands

B. Dwarfism

  1. Usually caused by abnormalities of growth hormone (GH) production or sensitivity
  2. Serum insulin like-growth factor 1 (IGF-1) levels are invariably low or zero
  3. Laron dwarfism is caused by mutations in GH receptor
  4. IGF-1 is in clinical testing for treatment of dwarfism resistant to GH
  5. GH itself can be used to treat disorders of stunted growth and some dwarfism
  6. Mutations in IGF-1 Receptor [28]
    1. Can lead to intrauterine growth retardation (IUGR)
    2. Subsequent growth may be retarded
    3. These patients will be resistant to GH or IGF-1 replacement

C. Congenital Adrenal Hyperplasia (CAH) [9,10,32]

  1. Group of autosomal recessive disorders with blocked cortisol synthetic activity
  2. Overall incidence is ~1:15,000 births
  3. Decreased cortisol and aldosterone secretion
  4. Chronic elevated ACTH leads to bilateral adrenal hyperplasia
  5. Precocious puberty can occur
  6. Forms of CAH
    1. Salt-losing - presents as life-threatening adrenal crisis age 2-3 weeks
    2. Simple virilizing (non-salt losing) - presents with early virilization within 5 years
    3. Both forms include ambiguous genitalia in girls
  7. Symptoms of Untreated CAH
    1. Life-threatening adrenal insufficiency (salt-losing form)
    2. Pseudo-precocious puberty
    3. Virilization of female genitalia
    4. Premature growth acceleration
    5. Premature epiphyseal fusion
    6. Adult short stature
    7. Hirsutism
  8. Goals of Treatment
    1. Normalize glucocorticoid and mineralocorticoid levels
    2. Suppress androgen production

D. Maturity Onset Diabetes Of The Young [12]

  1. Heterogeneous group of disorders of nonketotic hyperglycemia and diabetes mellitus
  2. Autosomal dominant inheritance
    1. Can be caused by mutations in at least 6 different genes
    2. Glucokinase (a glycolytic enzyme) mutations causes MODY 2
    3. Other genes implicated in MODY code for transcription factors
    4. Mutations in hepatocyte nuclear factor (HNF) 4 alpha (HNF 4a) cause MODY 1
    5. HNF 1a mutations cause MODY 3
    6. Insulin promoter factor 1 mutations cause MODY 4
    7. HNF 1ß mutations cause MODY 5
    8. Neurogenic differentiation factor 1 (NeuroD1, also BETA2) mutations cause MODY 6
  3. Onset usually <25 years of age
    1. Usually presents as mild hyperglycemia in nonobese young people
    2. Family history of diabetes mellitus common
    3. Diagnosis often delayed until adulthood
    4. Frank fasting hyperglycemia may not occur for years after onset of glucose intolerance
    5. Obesity is typically absent
  4. Treatment as for other Type 2 Diabetes Mellitus (DM) [27]
    1. HNF-1a deficiency diabetes is highly sensitive to sulfonylureas
    2. More insulin sensitive than general type 2 DM
    3. Response to metformin is inferior to that of generaly type 2 DM

E. Congenital Hyperinsulinism [13,14]

  1. Most common cause of recurrent hypoglycemia in infancy
  2. Presentation with seizures and/or coma
  3. Permanent brain damage may occur
  4. Various genetic causes have been identified:
    1. Sulfonylurea receptor (SUR1) mutations
    2. Inwardly rectifying potassium ion channel (Kir6.2) mutations
    3. These two mutations usually associated with focal islet-cell hyperplasia [14]
    4. Partial pancreatectomy may be effective for neonates with islet cell hyperplasia [14]
    5. Glucokinase gene mutations
    6. Glutamate dehydrogenase mutations - hypoglycemia and hyperammonemia

F. Abnormal Bilirubin Metabolism [15]

  1. Gilbert's Syndrome
    1. Increased bilirubin with fasting
    2. Normal conjugated bilirubin
    3. Benign disease
  2. Crigler-Najjar Syndrome Type 1
    1. No glucuronyl transferase
    2. Neonatal severe jaundice (kernicterus)
    3. Early death without treatment
    4. Liver transplantation or intravenous isolated hepatocyte infusions [16]
  3. Crigler-Najjar Syndrome Type 2
    1. Low glucuronyl transferase
    2. Relatively normal lifespan
  4. Dubin-Johnson Syndrome (DJS) [19]
    1. Chronic diopathic jaundice
    2. Benign, autosomal disorder
    3. Increased indirect bilirubin
    4. Vague constitutional or gastrointestinal symptoms
    5. Dark pigment in liver cells, melanin-like or epinephrine polymers
    6. DJS due to point mutation in MRP2 (canalicular multispecific organic ion transporter)
    7. Rotor Syndrome is similar to DJS, except that there is no dark pigment in liver cells

G. Primary Ciliary Dyskinesia (PCD) [18]

  1. Defective motility of cilia
  2. Abnormally low nasal nitric oxide
  3. Arginine, a precursor of nitric oxide, increases ciliary beat frequency in PCD

H. Proteus Syndrome [19]

  1. Popularly documented in the "Elephant Man"
  2. Somatic mutation leading to patchy, irregular overgrowth of body parts and cell lineages
  3. Likely due to mutation after early embyonic cell divisions leading to mosaicism
  4. Rare disorder, only affecting several people in USA and Europe
  5. Differential Diagnosis
    1. Klippel-Trenaunay Syndrome
    2. Hemihyperplasia
    3. Parkes Weber Syndrome
    4. Maffuci Syndrome
    5. Neurofibromatosis Type 1
    6. Epidermal Nevus Syndrome
    7. Bannayan Riley Ruvalcaba Syndrome
    8. Familial or Symmetric Lipomatosis
  6. Major medical and psychosocial consequences
  7. Surgical corrections of deformities is generally required

I. Trisomy 18 [20]

  1. Also called "Edward's Syndrome"
  2. One per 6000 live births
  3. Characteristics
    1. Low birth weight
    2. Mental retardation
    3. Cranial, cardiac, renal malformations
  4. Death usually within first year of life

J. Phenylketonuria (PKU) [31]

  1. Autosomal recessive trait due to phenylalanine hydroxylase (PAH) deficiency
    1. Cannot metabolize phenylalanine (Phe)
    2. Disease also called hyperphenylalaninemia
    3. Natural enzyme cofactor for PAH is tetrahydrobiopterin
  2. About 50% of patients have mild phenotypes
    1. Normal Phe blood levels 1.3-2.0mg/dL (80-120µmol/L)
    2. Mild hyperphenylalaninemia Phe blood levels 3-10mg/dL
    3. Atypical / mild PKU: 10-20mg/dL
    4. Classical PKU: >20mg/dL
  3. ~1:10,000 live births in North America (most detected on newborn screening)
  4. Failure to treat leads to irreversible mental retardation in 80-90% of persons
    1. Treatment should commence at birth and continue for at least 10-12 years
    2. Recommended that Phe levels be maintained <2-6mg/dL in children
    3. Recommended that Phe levels be maintained <10-20mg/dL in adults
    4. Many adults do not maintain low Phe diet and function normally
    5. Critically important that women maintain blood levels <10mg/dL during pregnancy
    6. Late onset neurologic signs can occur in a minority of (even treated) adult patients
  5. Treatment
    1. Low Phe containing diet
    2. Vegan-vegetarian fare: no meat, milk, cheese, eggs, nuts or bread AND
    3. Synthetic Phe-free formula with fats, essential amino acids, vitamins, minerals
    4. Sapropterin (tetrahydrobiopterin, Kuvan®) is the natural cofactor of PAH and is approved [41]
    5. Sapropterin 10mg/kg qd po for 6 weeks, lead to significant reductions blood Phe levels in ~45% of patients [22,39,41]
    6. May increase sapropterin dose to 20mg/kg after a month if phe levels do not decrease; the drug should be discontinued if no reduction in phe after 1 month at 20mg/kg [41]
    7. Main side effects are mild including rhinorrhea, headache, nausea, vomiting
    8. Risk of general and specific nutritional deficiencies and these should be monitored
    9. Frequent measurements of blood Phe levels recommended
    10. Treated patients are living >40 years with fairly normal lives
  6. Maternal PKU [21]
    1. Untreated maternal PKU increases risk for developmental problems in offspring
    2. This is particularly a problem during the first trimester
    3. Treatment during pregnancy may reduce developmental problems
    4. Maintain blood Phe levels <10mg/dL

K. Alkaptonuria [23]

  1. Deficiency of homogentisate 1,2-dioxygenase (HGO)
  2. Leads to accumulation homogentisic acid (HGA)
    1. HGA oxidizes to form melanin-like polymers
    2. Accumulation of HGA and metabolites in tissues
    3. Causes ochranosis and darkening of cartilaginous tissues
  3. Manifestations
    1. Bone, arthritis and joint destruction is main morbidity
    2. Joint replacement at mean age 55
    3. Cardiac valve deterioration then occurs, mean age 54 years
    4. Coronary artery calcification mean 59 years
    5. Renal stones at age 54
  4. Nitisinone (Orfadin®) inhibits HGA production
    1. Doses 0.7 - 2.8 mg po qd
    2. Reduced urinary HGA excretion 2.9 to 0.13 gm per day
    3. Plasma tyrosine levels rose with no clinical signs or symptoms
    4. Long term treatment has not been treated

L. Hallervorden-Spatz Syndrome [24]

  1. Autosomal recessive disorder associated with chromosome 20p13
  2. Dystonia, parkinsonism, iron accumulation in brain
  3. Most patients have mutations in pantothenate kinase 2 (PANK2)
    1. All patients with classic Hallervorden-Spatz Syndrome
    2. ~35% of patients with atypical Hallervorden-Spatz Syndrome
  4. T2-weighted magnetic resonance imaging (MRI) shows classic patterns
  5. Predicted levels of PANK2 correlate with disease severity

M. Del22q11 Syndrome [25]

  1. Most frequent chromosomal microdeletion syndrome
  2. Incidence 1 in ~4500 live births
  3. 3 megabase (MB) deletion on chromsome 22q11.2
  4. Phenotype
    1. Cardiac defects - tetrology of Fallot, septal defects, aortic arch anomalies, others
    2. T cell defects due to thymic hypoplasia
    3. Facial (cleft palate) abnormalities and conotruncal anomaly faces
    4. Hypocalcemia
  5. Over 30 genes mapped to deleted region
  6. Likely that TBX1 mutations (loss) responsible for del22q11.2 syndrome
  7. TBX1 is a T-box transcription factor likely responsible for major phenotypes in del22q11.2

N. Laminopathies [26]

  1. Mutations in the LMNA (laminin A/C) gene
  2. Share some features of Werner Syndrome (particularly atypical type)
  3. Emery-Dreifuss muscular dystrophy
  4. Limb-girdle muscular dystrophy type 1B
  5. Dilated cardiomyopathy type 1A
  6. Familial partial lipodystrophy
  7. Charcot-Marie-Tooth disease type 2
  8. Mandibuloacral dysplasia
  9. Hutchinson-Gilford Syndrome

O. Hutchinson-Gilford Syndrome [40]

  1. Progeroid (premature aging) syndrome (progeria)
  2. Rare disease with manifestations during childhood
  3. Average lifespan to 13 years with death usually due to cardiovascular disease or stroke
  4. Due to lamin A (LMNA, progerin) gene mutation
    1. This activates a novel mRNA splice site leading to abnormal lamin A protein
    2. Disrupts nuclear membrane and alters transcription
    3. Abnormal lamin A acccumulates
  5. Main Symptoms/Signs
    1. Sclerotic skin
    2. Joint contractures
    3. Bone abnormalities
    4. Growth impairment
    5. Cardiovascular: elevated blood pressure, reduced vascular compliance, adventitial thickening
    6. Central nervous system sequellae
  6. Growth hormone treatment increased height by 10% and weight by 50%

P. Retinitis Pigmentosa (RP) [36]

  1. Hereditary peripheral retinopathy
  2. Progressive loss of rod and cone photoreceptors
  3. Prevalence about 1:4000 persons, or ~1 million worldwide
  4. Genetic Disease
    1. Autosomal dominant (~35%), recessive (~55%), and X-linked (~10%) forms
    2. Over 45 genes for RP have been idenitified accounting for ~60% of RP
    3. Unidentified causes in ~40% of RP cases
  5. Genes associated with RP
    1. Rhodopsin (RHO): ~25% of dominant RP
    2. Alpha and ß subunits of rod cGMP phosphodiesterase
    3. Rod cGMP cation-gated channel protein alpha subunit
    4. Peripherin/RDS gene
    5. TULP1 and TULP 2 genes
    6. USH2A: ~20% of recessive RP
    7. RPGR gene: ~70% of X-linked RP
  6. Slowly Progressive Retinal Degeneration
    1. Loss of night vision in adolescence
    2. Loss of side vision in young adulthood
    3. Loss of central vision in later life
    4. Highly variable disorder
  7. Non-ocular disease present in ~25% of patients
    1. hearing impairment or loss
    2. Bardet-Biedl Syndrome: obesity, cognitive impairment, polydactyly, hypogenitalism, renal disease
  8. Interventions
    1. Vitamin A palmitate (15,000 IU/day) but not Vitamin E
    2. Omega-3 rich fish - diet of at least 1.4gm omega-3 fatty acids per week
    3. Slow disease progression in many patients
    4. Reduce exposure to light
    5. Carbonic anhydrase inhibitors can improve vision in patients with macular edema

Q. Short-Chain Acyl-Coenzyme A Dehydrogenase (SCAD) Deficiency [35]

  1. Autosomal recessive inborn error of mitochondrial fatty acid ß-oxidation
  2. Birth prevalence of ~1:50,000
  3. Most patients present <3 years old
  4. Nonspecific, generally uncomplicated symptoms, often transient and nearly all mild
  5. Developmental delay, epilepsy, behavioral disturbances, hypoglycemia
  6. Screening with increased C4-CoA, but not recommended at this time

R. Autosomal Diseases with Gonadal Abnormalities [4]

  1. Wilms' Tumor Gene (WT1)
    1. WT1 gene controls renal and gonadal development
    2. Frasier syndrome has gonadal dysgenesis and renal abnormalities
    3. WT1 splicing anomalies (KTS) lead to streak gonads coupled with nephrotic syndrome
    4. KTS (lysine/threonine/serine) mutations lead to testicular abnormalities
    5. WT1 mutations outside KTS region lead to later gonadal developmental abnormalities
    6. Denys-Drash syndrome - non-KTS mutations, poor testosterone production
  2. Steroidogenic Factor
    1. Steroidogenic factor 1 (SF-1) encodes transcription factor with unknown ligand
    2. SF-1 binds DNA and regulates various genes required for gonadal and adrenal development
    3. Consider SF-1 mutations in humans with adrenal and gonadal syndromes
  3. DAX1
    1. Nuclear receptor family of proteins, unknown ligand
    2. Mutations associated with adrenal hypoplasia and hypogonadotropic hypogonadism

S. Menkes Disease [41]

  1. Fatal neurodegenerative disorder of infancy
  2. Due to various mutations in copper transport gene ATP7A
  3. Neonatal diagnosis can be made by assessing plasma products of dopamine ß-hydroxylase
    1. Plasma dopamine, norepinephrine, dihydroxyphenylacetic acid, dihydroxyphenulglycol assessed
    2. Abnormal levels of these products suggests Menkes disease
    3. Early diagnosis followed by copper treatment improves mortality
  4. Early treatment with copper injections may prevent death and limit morbidity

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