Академический Документы
Профессиональный Документы
Культура Документы
1. Organic acidemias
2. Amino acid metabolism disorders
3. Urea cycle metabolism disorders
4. Fatty acid metabolism disordres
5. Carbohydrate metabolism disorders
6. Peroxisomal disorders
7. Purine metabolism disorders
8. Mineral metabolism disorders
9. Mucopolysaccharidoses
10. Lipid storage disorders
11. Hemochromatosis
12. Cystic fibrosis
MSUD - introduction
Infants with classic MSUD - normal at birth, but remain well for only a few
days
Vomiting or difficulty to feed - early symptoms
By the end of the first week - lethargic, progressive neurologic
deterioration
periods of flaccidity alternating with hypertonicity
abnormal eye movements, convulsions occur regularly
Finally apnea, coma, and death
MSUD - genetics
MSUD - screening
Rapid screening for MSUD - tandem MS - forms the basis for all of the
neonatal screening programs for this disease.
What is it?
Pregnancy
Babies born to mothers with PKU and uncontrolled phenylalanine levels significant risk of intellectual disability due to exposure to very high levels of
phenylalanine before birth
low birth weight
grow slowly
heart defects or other heart problems
small head size (microcephaly)
behavioral problems
risk of pregnancy loss.
The occurrence of PKU varies among ethnic groups and geographic regions
worldwide
In the United States, PKU occurs in 1 in 10,000 to 15,000 newborns.
In Poland 1 in 8000 newborns
Most cases of PKU are detected shortly after birth by newborn screening, and
treatment is started promptly result: the severe signs and symptoms of classic
PKU are rarely seen.
Testing
Testing
Newborn screening:
PAH deficiency is most commonly diagnosed upon routine screening of newborns.
PAH deficiency can be detected in virtually 100% of cases by newborn screening
utilizing the Guthrie card bloodspot obtained from a heel prick.
Testing
Clinical testing
Prevalence
Treatment of Manifestations
Restriction of dietary phenylalanine.
normalization of the concentrations of Phe and Tyr in the blood
Phe concentrations of 120-360 mol/L (2-6 mg/dL) or 40-240 mol/L (1-4 mg/dL) regarded as safe.
A diet restricted in Phe - initiated as soon as possible after birth and continued at
least into adolescence
The diet must be carefully monitored so that growth and nutritional status are
unaffected
Supplementation with BH4.
many individuals with PAH deficiency - responsive to the 6R-BH4 stereoisomer in
pharmacologic doses (20 mg/kg daily in divided oral doses)
the 6R-BH4 enhances in vivo phenylalanine hydroxylation and lowers plasma
phenylalanine concentration with improved tolerance of dietary phenylalanine
Treatment of Manifestations
Treatment in infancy.
A Phe-restricted diet
Breastfeeding with Phe-free formula
Intake of tyrosine and total amino acids
Avoid long periods of low blood Phe concentration - harmful to brain development.
Treatment in childhood.
Total amino acid consumption of 2 g/kg/day, 25 mg tyrosine/kg/day.
Treatment in adolescence and adulthood.
Various
Surveillance
Plasma Phe and Tyr concentrations - monitored regularly
No recommendations for surveillance
What to avoid?
Molecular Genetics
Gene symbol: PAH
Chromosomal locus: 12q23.2
Protein name: phenylalanine-4-hydroxylase
13 exons
90 kilobases
2.4-kb mature messenger RNA
31 different polymorphisms neutral effect
Alkaptonuria
deficiency of homogentisate 1,2-dioxygenase - an enzyme that converts
homogentisic acid (HGA) to maleylacetoacetic acid in the tyrosine degradation
pathway.
major features: HGA in urine, ochronosis (bluish-black pigmentation in connective
tissue), arthritis of the spine and joints.
oxidation of the HGA - melanin-like product dark urine upon standing
ochronosis: after age 30 years;
arthritis: third decade.
other manifestations: pigment deposition, aortic or mitral valve calcification or
regurgitation and occasionally aortic dilatation, renal stones, and prostate stones.
Diagnosis/testing
detection of a significant amount of HGA in the urine by GCMS
the amount of HGA excreted per day - between 1-8 g
a normal 24-hour urine sample - 20-30 mg of HGA
Management
Treatment of manifestations:
management of joint pain tailored to the individual;
physical and occupational therapy - maintain muscle strength and flexibility;
knee, hip, and shoulder replacements when needed;
surgical intervention for prostate stones and renal stones as needed.
Surveillance:
in individuals over age 40 years - echocardiography to detect aortic dilation, aortic or
mitral valve calcification, and regurgitation; CT to detect coronary artery calcification.
Agents/circumstances to avoid: physical stress to the spine and large joints,
heavy manual labor or high-impact sports - reduce progression of severe arthritis
Genetic counseling
autosomal recessive disease
at conception - sib of an affected individual:
25% chance of being affected
50% chance of being an asymptomatic carrier
25% chance of being unaffected and not a carrier
MCAD
most common disorder of fatty acid oxidation
1 in 6000 to 10 000 caucasian births
MCAD - genetics
MCAD - Prevalence
Treatment of Manifestations
Galactose-1-phosphate uridyl
transferase, the site of the enzyme
defect in patients with galactosemia.
The brackets indicate the uridyl and
glucose-1-phosphate moieties of
UDPG which have split at the arrow in
the uridyl transferase reaction,
transferring the uridyl group from G-1-P
of UDPG to galactose-1-phosphate
(Gal-1-P) to form
uridinediphosphogalactose
(UDPGal).
Galactosemia - sepsis
Galactosemia - genetics
Galactose
Lesch-Nyhan disease
male infants - normal at birth, develop normally for the first 6 to 8 months
first sign - orange crystals or orange sand in the diapers (crystalluria)
defective motor development - evident in the second six months of life
failure to reach developmental milestones
patients do not learn to walk, and must have some support even to sit
unaided
but do learn to sit in a chair if fastened securely
involuntary movements - 100 percent of patients
self-injurious behaviour
Tay-Sachs disease
Disease characteristics:
Hexosaminidase A deficiency
neurodegenerative disorder caused by intralysosomal storage of the specific
glycosphingolipid -GM2 ganglioside.
Tay-Sachs disease (acute infantile):
progressive weakness
loss of motor skills
decreased attentiveness
neurodegeneration
seizures
blindness
spasticity
death, usually before age 5
Tay-Sachs disease
The juvenile (subacute) and adult-onset variants
later onsets
slower progression
more variable neurologic findings: progressive dystonia, spinocerebellar
degeneration, motor neuron disease, bipolar form of psychosis.
Diagnosis/testing
demonstration of absent to near-absent beta-hexosaminidase A (HEX A) enzymatic
activity in the serum or white blood cells of a symptomatic individual in the presence
of normal or elevated activity of the beta-hexosaminidase B (HEX B) isoenzyme
Mutation analysis of the HEXA gene: for genetic counseling purposes to
1) to distinguish pseudodeficiency alleles from disease-causing alleles in individuals
with apparent deficiency of HEX A enzymatic activity
2) to identify specific disease-causing alleles in affected individuals
Management
Treatment:
supportive
provide adequate nutrition and hydration
manage infectious disease
protect the airway
control seizures
Seizure control:
conventional anticonvulsant drugs: benzodiazepines, phenytoins, barbiturates
progressive
change in type and severity
Management
adult-onset hexosaminidase A deficiency with psychiatric manifestations:
conventional antipsychotic or antidepressant therapy
treatment with lithium salts
electroconvulsive therapy - beneficial in ameliorating psychotic depression.
Genetic counseling
autosomal recessive manner
At conception, each sib of an affected individual:
25% chance of being affected
50% chance of being an asymptomatic carrier
25% chance of being unaffected and not a carrier
Prevalence
previously one in 3600 Ashkenazi Jewish births
carrier rate for TSD: one in 30 among Jewish Americans of Ashkenazi extraction
(Central and Eastern Europe).
now the incidence of TSD in the Ashkenazi Jewish population - reduced by greater
than 90% - result of extensive genetic counseling of carriers identified through
carrier screening programs and monitoring of at-risk pregnancies
Among Sephardic Jews and all non-Jews - 100 times less common - carrier
frequency (between 1/250 and 1/300)
all ethnic, racial, and religious groups.
Certain populations isolated genetically: French Canadians of Quebec, Cajuns from
Louisiana and the Old Order Amish in Pennsylvania - carry HEXA mutations with
frequencies comparable to or even greater than Ashkenazi Jews.
Molecular genetics
35,000 bp
contains 14 exons
Cystic fibrosis
recognised 1936
accumulation of thick mucous secretions
blockage of the airways
secondary infection
significant cause of chronic ill health and mortality in childhood and early adult life.
Icidence rate - 1 in 2000 to 1 in 3000
African-Americans (1 in 15000)
Asian-Americans (1 in 31 000).
Clinical features
Diagnosis/testing
diagnosis of cystic fibrosis - established in individuals with one or more characteristic
phenotypic features of CF
abnormality in CFTR function:
presence of two disease-causing mutations in the CFTR gene
abnormal sweat chloride values (>60 mEq/L)
transepithelial nasal potential difference (NPD) measurements characteristic of CF
Management
Treatment of manifestations:
treatment/prevention of pulmonary complications using oral or inhaled antibiotics
bronchodilators
anti-inflammatory agents
mucolytic agents
chest physiotherapy
lung or heart/lung transplantation in selected patients
topical steroids
surgical intervention for nasal/sinus symptoms
special infant formulas to enhance weight gain
oral pancreatic enzyme replacement
additional fat-soluble vitamins and zinc
management of CF-related diabetes mellitus (CFRD) by an endocrinologist
assisted reproductive technologies (ART) for male infertility
Surveillance
Agents/circumstances to avoid
respiratory irritants (smoke, dust)
respiratory infectious agents (especially viruses)
dehydration
GENETICS
autosomal recessive inheritance
most serious autosomal recessive disorder European origin
possible explanations: multiple CF loci and high mutation rate
chromosome 7q31
CF transmembrane conductance regulator (CFTR)
250 kb
27 exons
1900 mutations and polymorphisms to date
DelF508
delF508
Dele2,3(21kb)