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MG Medical Genetics
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Spencer van Mil, chapter editor

Sheliza Halani and Taraneh Tofighi, associate editors
Arnav Agarwal and Sukhmani Sodhi, EBM editors
Dr. Hanna Faghfoury and Dr. Joyce So, staff editors

Acronyms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Introduction to Genetics. . . . . . . . . . . . . . . . . . . . . 2
Background
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Pedigrees
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Genetic Testing and Counselling

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Dysmorphisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Congenital Anomalies
Approach to the Dysmorphic Child

Syndromes and Diseases . . . . . . . . . . . . . . . . . . . . 5

Large Genomic Changes
Single Gene Disorders
Metabolic Diseases

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
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Medical Genetics MG1 Toronto Notes 2018

MG2 Medical Genetics Toronto Notes 2018
Acronyms

Acronyms
CF cystic fibrosis ONTD open neural tube defect
CNV copy number variation PKU phenylketonuria
FISH fluorescence in situ hybridization SCID severe combined immunodeficiency
FTS first trimester screening US ultrasound
IPS integrated prenatal screening

Introduction to Genetics
Background
Terms
• Penetrance: extent that a gene is observably expressed in an individual that carries it
• Expressivity: extent of gene expression
• Genetic heterogeneity: genetic disorder can arise from different allele/locus mutations
• Phenotypic heterogeneity: mutations in the same gene resulting in multiple diverse clinical
manifestations and degree of severity
• Imprinting: epigenetic process that involves methylation or acetylation of DNA, affecting gene
expression
• Uniparental disomy: two full or partial copies of a chromosome from one parent and no chromosome
from the other parent

Mendelian Inheritance
• disorders caused by mutation of one or both copies (alleles) of a gene, inherited in one of two patterns
■■ autosomal: when disorder is caused by genes on one of 22 pairs of autosomes (chromosomes 1-22)
■■ X-linked: when disease is caused by a gene on the X chromosome

Triplet Repeat Expansions

• disorder in which trinucleotide repeats in certain genes exceed the normal number and result in altered
gene expression or production of an abnormal protein (e.g. Fragile X syndrome, Huntington's disease)

Imprinting Disorders
• imprinted genes are expressed entirely from either the maternal or paternal allele, depending on the
gene (parent-of-origin gene expression)
• occur when a mutation disrupts the normally expressed allele of imprinted gene (e.g. Prader-Willi
syndrome, Angelman syndrome, Beckwith-Wiedemann syndrome) or through uniparental disomy of
the normally silenced allele

Mitochondrial Disorders
• disorders caused by mutations of the DNA present in mitochondria or nuclear genes whose protein
products are important for mitochondrial function
• inheritance pattern of mitochondrial DNA mutations: mother passes on the defect to all her children;
father cannot pass on defect since embryo only receives mitochondria from the mother (in the egg)

Copy Number Variation

• difference in the amount of genetic material
■■ decrease: deletion of a chromosomal region, leaving only one copy of the genetic material in that
region (e.g. 22q11.2 deletion syndrome due to deletion on chromosome 22)
■■ increase: duplication of a chromosomal region, resulting in more than two copies of the genetic
material in that region (e.g. Potocki-Lupski syndrome due to duplication of chromosome 17p11.2)
• CNVs can be part of normal range of genetic variation
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Introduction to Genetics
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Pedigrees
• diagrams that show the pattern/distribution of phenotypes for a genetic disorder within a family, often
across multiple generations

Male, unafffected Married/Partners Spontaneous Abortion

Termination of Pregnancy
Female, unaffected Divorced/Separated
Ectopic Pregnancy
ECT
Gender Unknown,
Consanguinity
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unaffected
Adopted Sibling
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Deceased Infertility
Siblings (listed from
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left to right (oldest to

Affected Individual youngest)
No Offspring
by choice Dizygous Twins
Affected Individual
≥2 conditions (fraternal)
P P Pregnancy
Carrier not likely to Monozyous Twins
manifest disease (identical)
Stillbirth (write SB
Carrier unaffected at and gestational age
this time but could SB SB if known)
manifest disease later

Figure 1. Common pedigree symbols

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Genetic Testing and Counselling

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• microarray analysis
■■ array comparative genomic hybridization (CGH): a collection of DNA probes attached to a solid
surface to which test DNA hybridizes in order to determine copy number of DNA regions
■■ microarray analysis can identify small deletions or duplications of genetic material anywhere in the
genome
■■ commonly indicated when there is developmental delay OR two or more congenital anomalies
• FISH (fluorescence in situ hybridization): a DNA probe used to identify a gain or loss of chromosomal
material
• karyotype: microscopic analysis of chromosomes with a special stain that shows large changes in the Whole-Genome Sequencing Expands
number or structure of chromosomes; can detect large CNVs Diagnostic Utility and Improves Clinical
Management in Paediatric Medicine
• Sanger sequencing: the ‘gold-standard’ method for identification of single nucletotide variants in short Genomic Med 2016;1:15012
DNA sequences (e.g. the exons of the gene(s) known to cause suspected syndrome) While the standard of care for neurodevelopmental
• next-generation sequencing: high-throughput method to sequence exomes or whole-genomes; useful and congenital malformations is chromosome
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when genetic syndrome is suspected, but diagnosis is unclear: increasingly used for multi-gene test microarray analysis for copy-number variations,
panels whole exome sequencing allows the identification
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of sequence-level mutations across all known

• prenatal screening coding genes. Whole genome sequencing has
■■ offer optional prenatal screening before diagnostic testing
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been previously associated with a diagnostic yield

■■ first trimester screening (FTS) of ~25% for neurological disorders or congenital
◆◆ biochemistry (b-hCG, PAPP-A) anomalies. A recent study published in Genomic
◆◆ US estimate of gestational age and measurement of nuchal translucency Medicine has demonstrated that whole genome
sequencing exceeds other technologies in detecting
◆◆ screen for trisomy 21 and 18 genetic variants with a 34% diagnostic yield, a
◆◆ done between 11 and 14 wk, sensitivity=80-85% four-fold increase in molecular diagnosis relative to
■■ integrated prenatal screening (IPS) chromosome microarray analysis and a two-fold
◆◆ ONTD, trisomy 21 and 18 increase relative to all genetic testing protocols.
◆◆ use results from FTS and combine with additional biomarkers completed between 15-21 weeks These results suggest that whole genome
sequencing may be used as a first-tier molecular
(inhibin A, unconjugated estradiol, AFP, 2nd trimester b-hCG) test in individuals with development delays and
◆◆ improved sensitivity, reduced false positive rate compared to FTS congenital abnormalities, with a higher diagnostic
■■ fetal anatomy scan yield than conventional genetic testing and
◆◆ US at 18-20 wk decreased time to genetic diagnosis.
• newborn screening
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■■ detect potentially fatal, treatable disorders before symptoms begin to allow for early therapy
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■■ performed on all newborns in Canada

■■ heel puncture to collect blood
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■■ screens for CF, congenital hypothyroidism, congenital adrenal hyperplasia, SCID,

hemoglobinopathies, metabolic diseases, etc.
MG4 Medical Genetics Toronto Notes 2018
Dysmorphisms

Dysmorphisms
Congenital Anomalies
Minor and Major Anomalies
• minor anomaly: an unusual anatomic feature that is of no serious medical or cosmetic consequence to
the patient
• major anomaly: anomaly that creates significant medical, surgical, or cosmetic problems for the patient

Mechanism for Anomalies

• malformation: results from an intrinsically abnormal developmental process (e.g. polydactyly)
• disruption: results from the extrinsic breakdown of, or interference with, an originally normal
developmental process (e.g. amniotic band disruption sequence)
• deformation: alteration of the final form of a structure by mechanical forces (e.g. Potter deformation
sequence)
• dysplasia: abnormal development that results in abnormal organization of cells into tissues (e.g. bone
dysplasia)

Multiple Anomalies VACTERL Association

• association: non-random occurrence of multiple independent anomalies that appear together more V Vertebral dysgenesis
than would be predicted by chance but are not known to have a single etiology (e.g. VACTERL) A Anal atresia (imperforate anus)
• sequence: related anomalies that come from a single initial major anomaly or precipitating factor that ± fistula
C Cardiac anomalies
changes the development of other surrounding or related tissues or structures (e.g. Potter sequence or T-E TracheoEsophageal fistula
Pierre-Robin sequence) ± esophageal atresia
• syndrome: a pattern of anomalies that occur together and are known or thought to have a single cause R Renal anomalies
(e.g. Down syndrome) L Limb anomalies

Approach to the Dysmorphic Child

• congenital abnormalities are the most common cause of infant death in developed countries

General Approach to the Dysmorphic Child

• Are the anomalies major or minor?
• What is the mechanism underlying the anomaly?
• Do the anomalies fit as part of an association, sequence, or syndrome?

History
• prenatal/obstetrical history (see Obstetrics, OB4) with particular attention to potential teratogenic
exposures, developmental history (see Pediatrics, P22), and past medical history
• complete 3 generation family pedigree: health history, consanguinity, stillbirths, neonatal deaths,
specific illnesses, intellectual disability, multiple miscarriages, ethnicity

Physical Exam

Face: gestalt

Ears: structure, size,

Skull: contour and symmetry
placement, rotation
Nose: nasal bridge, nostrils Hair: texture, pattern
Philtrum: length, shape
Eyes: distance apart, brows, lashes,
Mouth: lips, palate, tongue, teeth
folds, creases, coloboma, fundus
Spine: scoliosis, kyphosis Chin: size, position
Skin: hair tufts, sacral
dimples, sinus Neck: webbed, redundant nuchal skin

Limbs: proportions, amputations Thorax: shape, size, nipple spacing

Genitalia: ambiguous

Hands and Feet: creases,

structure, nails

Growth parameters (head circumference, height, weight)

Figure 2. Physical exam of the dysmorphic child

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Syndromes and Diseases
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Investigations
• screening for TORCH infections
• serial photographs if child is older
• x-rays for bony abnormalities
• cytogenetic studies
■■ karyotype if recognized aneuploidy syndrome Check the umbilical cord for 2 arteries and 1 vein.
■■ chromosomal microarray analysis (array comparative genomic hybridization) if developmental The presence of a single umbilical artery may be
delay OR two or more congenital anomalies associated with other congenital anomalies
■■ FISH if aneuploidy syndrome (e.g. trisomy 13, 18 or 21) suspected
• biochemistry: various biochemical profiles, specific enzyme assays
• single gene testing, multi-gene panel testing

Management
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• prenatal counselling and assessing risk of recurrence

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• referral for specialized pediatric or genetic care for symptomatic management

• specific treatments are available for certain metabolic disorders and genetic syndromes
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■■ metabolic disorders: enzyme replacement therapy, substrate reduction therapy, etc. (e.g. low-protein
diet in PKU patients)
■■ genetic syndromes: e.g. mTOR inhibitors in tuberous sclerosis

Syndromes and Diseases

Large Genomic Changes
Table 1. Trisomy Chromosomal Syndromes
Trisomy 21 Trisomy 18 Trisomy 13
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Disease Down syndrome Edwards’ syndrome Patau syndrome

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Incidence 1:600-800 births 1:6,000 live births 1:10,000 live births

Most common abnormality of autosomal chromosomes F:M = 3:1
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Rises with advanced maternal age from 1:1,500 at age 20

to 1:20 by age 45
Cranium/Brain Mild microcephaly, flat occiput, 3rd fontanelle, Microcephaly, prominent occiput Microcephaly, sloping forehead, occipital
brachycephaly scalp defect, holoprosencephaly
Eyes Upslanting palpebral fissures, inner epicanthal folds, Microphthalmia, hypotelorism, iris coloboma, Microphthalmia, corneal abnormalities
speckled iris (Brushfield spots), refractive errors (myopia), retinal anomalies
acquired cataracts, nystagmus, strabismus
Ears Low-set, small, overfolded upper helix, frequent AOM, Low-set, malformed Low-set, malformed
hearing loss
Facial Features Protruding tongue, large cheeks, low flat nasal bridge, Cleft lip/palate 60-80% cleft lip and palate
small nose Small mouth, micrognathia
Skeletal/MSK Short stature Short stature Severe growth retardation
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Excess nuchal skin Clenched fist with overlapping digits, hypoplastic Polydactyly, clenched hand
Joint hyperflexibility (80%) including dysplastic hips, nails, clinodactyly, polydactyly
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vertebral anomalies, atlantoaxial instability

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Cardiac Defect 50%, particularly atrioventricular septal defect 60% (VSD, PDA, ASD) 80% (VSD, PDA, ASD)
GI Duodenal/esophageal/anal atresia, TEF, Hirschsprung’s Hernia, TEF
disease, chronic constipation
GU Cryptorchidism, rarely fertile Polycystic kidneys, cryptorchidism Polycystic kidneys
CNS Hypotonia at birth Hypertonia Hypo- or hypertonia
Low IQ, developmental delay, hearing problems Seizures, deafness
Onset of Alzheimer’s disease in 40s Severe developmental delay

Other Features Transverse palmar crease, clinodactyly, and absent middle SGA Single umbilical artery
phalanx of the 5th finger Rocker-bottom feet Midline anomalies: scalp, pituitary, palate,
1% lifetime risk of leukemia heart, umbilicus, anus
Polycythemia Rocker-bottom feet
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Hypothyroidism
Prognosis: long-term management per AAP Guidelines 13% 1-year survival, 10% ten-year survival 20% 1-year survival, 13% ten-year survival
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Prognosis/
Management (Health Supervision of Children with Down syndrome), Profound intellectual disability in survivors Profound intellectual disability in survivors
recommend chromosomal analysis, CBC, Echo, yearly
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thyroid test, atlanto-occipital x-ray at 2 yr, sleep study,

hearing test, and ophthalmology assessment
MG6 Medical Genetics Toronto Notes 2018
Syndromes and Diseases

Table 2. Common Genetic Disorders Involving the Sex Chromosomes

Fragile X Syndrome Klinefelter Syndrome Turner Syndrome
Genotype X-linked 47,XXY (most common) 45,X (most common)
Genetic anticipation 48,XXXY, 49,XXXXY
CGG trinucleotide repeat on X chromosome
measurable by molecular analysis
Incidence 1:3,600 males, 1:6,000 females 1:1,000 live male births 1:4,000 live female births
Most common heritable cause of intellectual Increased risk with advanced maternal age Risk not increased with advanced maternal age
disability in boys
Phenotype Overgrowth: prominent jaw, forehead, and nasal Tall, slim, underweight Short stature, short webbed neck, low posterior hair
bridge with long and thin face, large protuberant No features prepuberty line, wide carrying angle
ears, macroorchidism, hyperextensibility, and high Postpuberty: male may suffer from developmental Broad chest, widely spaced nipples
arched palate delay, long limbs, gynecomastia, lack of facial Lymphedema of hands and/or feet, cystic hygroma in
Complications: seizures, scoliosis, mitral valve hair newborn with polyhydramnios, lung hypoplasia
prolapse Coarctation of aorta, bicuspid aortic valve
Renal and cardiovascular abnormalities, increased
risk of HTN
Less severe spectrum with mosaic
IQ and Behaviour Mild to moderate intellectual disability, 20% of Mild intellectual disability Mild intellectual disability to normal intelligence
affected males have normal IQ Behavioural or psychiatric disorders – anxiety,
ADHD and/or autism shyness, aggressive behaviour, antisocial acts
Female carriers may show intellectual impairment
Male carriers may demonstrate tremor/ataxia
syndrome in later life
Gonad and Premutation carrier females at risk of developing Infertility due to hypogonadism/hypospermia Streak ovaries with deficient follicles, infertility,
Reproductive premature ovarian failure primary amenorrhea, impaired development of
Function secondary sexual characteristics
Diagnosis/ Molecular testing of FMR1 gene: overamplification Increased risk of germ cell tumours and breast Normal life expectancy if no complications
Prognosis/ of the trinucleotide repeat, length of segment cancer Increased risk of X-linked diseases
Management is proportional to severity of clinical phenotype Management: testosterone in adolescence Management: Echo, ECG to screen for cardiac
(genetic anticipation) malformation
GH therapy for short stature
Estrogen replacement at time of puberty for
development of secondary sexual characteristics

Table 3. Other Genetic Syndromes

22q11.2 Deletion
Syndrome
Genotype Microdeletions of
chromosome region
22q11.2
Incidence 1:4000; Second most
common genetic diagnosis
(next to Down syndrome)
Clinical Features “CATCH 22”
Cyanotic CHD
Anomalies: craniofacial
anomalies, micrognathia
and low set ears
Thymic hypoplasia:
immunodeficiency
Cognitive impairment
Hypoparathyroidism,
hypocalcemia
22q11 microdeletions
High risk for schizophrenia
and other psych disorders
Prader-Willi Syndrome
Lack of expression of genes
on paternal chromosome
15q11-13 due to deletion,
maternal uniparental disomy
of chromosome 15, or
imprinting defect
1:15,000
“H3O”: Hypotonia and
weakness, Hypogonadism,
obsessive Hyperphagia,
Obesity
Short stature, almond-shaped
eyes, small hands and feet
with tapering of fingers
Developmental delay
(variable)
Hypopigmentation, type 2 DM
Angelman Syndrome
Lack of expression of genes
on maternal chromosome
15q11-13 due to deletion
or inactivation or paternal
uniparental disomy
1:10,000
Ataxia with severe intellectual
disability, seizures,
tremulousness, hypotonia
Midface hypoplasia, fair hair,
uncontrollable laughter
Noonan Syndrome CHARGE Syndrome
Autosomal dominant with 2/3 of children with
variable expression CHARGE have been found
PTPN11 mutation most to have a CHD7 mutation on
common cause but multiple chromosome 8
genes known
1:2,000 male and female 1:10,000
live births
Short stature, webbed “CHARGE”
neck, triangular facies, C Coloboma
hypertelorism, low set ears, H congenital Heart disease
epicanthal folds, ptosis, A choanal Atresia
pectus excavatum R mental Retardation
Right-sided CHD, pulmonary G GU anomalies
stenosis E Ear anomalies
Increased risk of
hematological cancers,
moderate intellectual
disability, delayed puberty
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Table 4. Familial Cancer Syndromes

Syndrome
Li-Fraumeni Syndrome
Lynch Syndrome (HNPCC)
FAP
Hereditary Breast and Ovarian
Cancer Syndrome
Von Hippel-Lindau Syndrome
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Gene Associated Cancers
TP53 Breast, osteosarcoma, leukemia, soft tissue carcinoma, and
numerous other cancers
MSH2, MLH1, MSH6, Colorectal, endometrial, ovarian, renal, pancreatic, liver/biliary
PMS2, EPCAM duct, stomach, brain, breast
APC Colorectal, small intestine/stomach tumours
BRCA1, BRCA2 Female: breast, ovarian, pancreatic
Male: prostate, breast, pancreatic
VHL Kidney + tumours (e.g. pheochromocytoma)

Cowden Syndrome PTEN Breast, thyroid, endometrial

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NF
Type 1
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NF1 Astrocytoma, optic glioma, neurofibroma, leukemia

Type 2
NF2 Vestibular schwannoma, meningioma, ependymoma,
astrocytoma

Single Gene Disorders

CYSTIC FIBROSIS
• see Respirology, R12 and Pediatrics, P82

SICKLE CELL DISEASE

• see Hematology, H20
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DUCHENNE MUSCULAR DYSTROPHY

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Epidemiology
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• 1:4,000 males

Etiology
• one type of muscular dystrophy characterized by progressive skeletal and cardiac muscle degeneration
• X-linked recessive: 1/3 spontaneous mutations, 2/3 inherited mutations
• missing structural protein (dystrophin) → muscle fibre fragility → fibre breakdown → necrosis and
regeneration

Clinical Presentation
• proximal muscle weakness by age 3, positive Gower’s sign, waddling gait, toe walking
Gower’s Sign
• pseudohypertrophy of calf muscles (muscle replaced by fat) and wasting of thigh muscles Child uses hands to “climb up” the legs to
• decreased reflexes move from a sitting to a standing position
• non-progressive delayed motor and cognitive development (dysfunctional dystrophin in brain)
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• cardiomyopathy
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Diagnosis
• molecular genetic studies of dystrophin gene (DMD) (first line)
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• family history (pedigree analysis)

• increased CK (50-100x normal) and lactate dehydrogenase
• elevated transaminases
• muscle biopsy, EMG

Management
• supportive (e.g. physiotherapy, wheelchairs, braces), prevent obesity
• cardiac health monitoring and early intervention
• bone health monitoring and intervention (vitamin D, bisphosphonates)
• steroids (e.g. prednisone or deflazacort)
• surgical (for scoliosis)
• gene therapy trials underway
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Complications
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• patient usually wheelchair-bound by 12 yr of age

• early flexion contractures, scoliosis, osteopenia of immobility, increased risk of fracture
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• death due to pneumonia/respiratory failure or CHF in 2nd-3rd decade

MG8 Medical Genetics Toronto Notes 2018
Syndromes and Diseases

Metabolic Diseases
• inherited disorders of metabolism; often autosomal recessive
• infants and older children may present with FTT or developmental delay
• organelle disorders can present with dysmorphism
• universal newborn screening in Ontario includes metabolic disorders

Table 5. Metabolic Disorders

Organic and Amino Carbohydrate Fatty Acid Disorders Organelle Disorders
Acid Disorders Disorders
Examples of PKU Galactosemia MCAD deficiency Mucopolysaccharidosis
Conditions Tyrosinemia GSDs: von Gierke’s, Carnitine deficiency Congenital disorders of
Homocystinuria Pompe’s, Cori’s, glycosylation
MSUD Andersen, McArdle Lysosomal storage diseases:
Alkaptonuria Hurler’s, Niemann-Pick, Tay-
Urea cycle defects Sachs, Gaucher, Fabry, Krabbe
Clinical Irritability, lethargy, poor Vomiting and acidosis Lethargy, poor feeding Seizures/early-onset severe
Manifestations feeding after feeding initiation Seizures, coma epilepsy
Seizures Growth retardation, FTT Symptoms triggered by Chronic encephalopathy
Intellectual disability fasting Developmental delay
Vomiting and acidosis Liver dysfunction Bone crises (Gaucher)
after feeding initiation Sudden infant death Deafness, blindness
Sweet-smelling urine
(MSUD)
Laboratory Hypoglycemic Hypoglycemia, Hypoketotic Elevated urine oligosaccharides
Findings hyperammonemia, hyperlipidemia (GSD) hypoglycemia (oligosaccharidoses)
high anion gap (organic Elevated free fatty acids and glycosaminoglycans
acidemia) (mucopolysaccharidoses)
Normoglycemic Enzyme deficieny
hyperammonemia,
normal anion gap (urea
cycle defects)
Physical Exam Hypotonia/hypertonia Infantile cataracts Hepatomegaly Dysmorphic facial features
Microcephaly, musty (galactosemia) Hypotonia Macrocephaly (Tay-Sachs,
odour, eczema, Hepatomegaly Hurler’s)
hypopigmentation (PKU) Muscle weakness/ Hepatosplenomegaly (Niemann-
Dark urine, pigmented cramping Pick type A/B/C, not Tay-Sachs)
sclerae, arthralgias Cherry-red spot on macula
(alkaptonuria) (Niemann-Pick type A/B, Tay-
Lens subluxation, Sachs, Gaucher’s)
marfanoid appearance Corneal clouding (Hurler’s)
(homocystinuria) Infantile cataract (Fabry)
Peripheral neuropathy (Fabry,
Krabbe)
Spasticity

Initial Investigations
• important to send lab studies at initial presentation in order to facilitate immediate diagnosis and
treatment
• check newborn screening results
• electrolytes, ABGs (calculate anion gap, rule out acidosis)
• CBC with differential and smear
• blood glucose (hypoglycemia seen with organic acidemia, fatty acid oxidation defects, and GSDs)
• lactate, ammonium (hyperammonemia with urea cycle defects), plasma Ca2+ and Mg2+
• routine urinalysis: ketonuria must be investigated
• carnitine levels with acylcarnitine profile
• others: urate, urine nitroprusside, plasma amino acid screen, urine organic acids, CSF glycine, free fatty
acids (3-β-hydroxybutyrate ratio >4 in fatty acid oxidation defect)
• storage diseases: urine mucopolysaccharide and oligosaccharide screen

Treatment
• varies according to inborn error of metabolism
• dietary restrictions, supplementation, enzyme replacement therapy, gene therapy, liver transplant, stem
cell transplant
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References
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PHENYLKETONURIA

Epidemiology
• 1:10,000; autosomal recessive disease

Etiology
• deficiency of phenylalanine hydroxylase prevents conversion of phenylalanine to tyrosine leading to
build up of toxic metabolites
• mothers who have PKU may have infants with congenital abnormalities

Clinical Presentation
• baby is normal at birth, then develops a musty odour, eczema, hypertonia, tremors, and mental Metabolic disease must be ruled out in any
retardation newborn who becomes acutely ill after a period
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of normal behaviour and development or with a

• hypopigmentation due to low tyrosine (fair hair, blue eyes) Reffamily history of early infant death even if the
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newborn screen is negative

Management
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• PKU screening at birth

• dietary restriction of phenylalanine starting within the first 10 d of life
• duration of dietary restriction controversial – lifelong or until end of puberty; should be resumed
during pregnancy to maintain normal phenylalanine levels
• large neutral amino acid (tyrosine) replacement, BH4 enzyme treatment, phenylalanine lyase treatment
are other options

GALACTOSEMIA

Epidemiology
• 1:60,000; autosomal recessive disease

Etiology
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• most commonly due to deficiency of galactose-1-phosphate uridyltransferase leading to an inability to

process lactose/galactose
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Clinical Presentation
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• signs of liver and renal failure, jaundice, FTT, and cataracts with ingestion of lactose/galactose

Management
• elimination of galactose from the diet (e.g. dairy, breast milk)
• most infants are fed a soy-based diet

Complications
• increased risk of sepsis, especially E. coli
• if the diagnosis is not made at birth, liver and brain damage may become irreversible

References
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Amato RSS. Nelson’s essentials of pediatrics, 4th ed. Philadelphia: WB Saunders, 2002. Human genetics and dysmorphology. 129-146.
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Blake KD, Prasad C. CHARGE syndrome, orphanet. J Rare Diseases 2006;1.

Biggar W. Duchenne muscular dystrophy. Pediatr Rev 2006;27:83-88.
Chudley AE, Conry J, Cook JL, et al. Fetal alcohol spectrum disorder: Canadian guidelines for diagnosis. CMAJ 2005;172(5 Suppl):S1-21.
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Elieff, M. P., Lopez-Beltran, A., Montironi, R., & Cheng, L. (2008). Familial cancer syndromes. In Molecular genetic pathology (pp. 449-466). Humana Press.
Grati, F. R., Malvestiti, F., Ferreira, J. C., Bajaj, K., Gaetani, E., Agrati, C., ... & Maggi, F. (2014). Fetoplacental mosaicism: potential implications for false-positive and
false-negative noninvasive prenatal screening results. Genetics in Medicine, 16(8), 620-624.
Moeschler JB, Shevell M. Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics 2014
Sep;134(3):e903-18. doi:10.1542/peds.2014-1839.
Nicholson JF. Nelson’s essentials of pediatrics, 4th ed. Philadelphia: WB Saunders, 2002. Inborn errors of metabolism. 153-178.
Sobel, E., & Lange, K. (1996). Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. American journal of human
genetics, 58(6), 1323.
Therrell, B. L., & Adams, J. (2007). Newborn screening in North America. Journal of inherited metabolic disease, 30(4), 447-465.
Vissers LE, van Ravenswaaij CM, Admiraal R, et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 2004;36:955-957.
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