Monogenic diseases.

Pathogenetic treatment of
hereditary orphan diseases
 Hereditary diseases - diseases, the
occurrence and development of which is
associated with changes in the genetic
material - gene, chromosomal or genomic
mutations.

The prevalence of hereditary diseases among

newborns: 5-5.5%

Genetic factors determine

20-30% of infant mortality,
40-50% of spontaneous abortions and miscarriages,
50% of cases of congenital deafness
70% - congenital blindness,
80% - mental retardation
 Genetic classification of hereditary
diseases

1. Monogenic diseases are caused by changes in

genes.
2. Chromosomal diseases caused by changes in
the number or structure of chromosomes.
3. Complex diseases are caused by interaction of
many genes and environmental factors.
4. Diseases with other types of inheritance
(mitochondrial diseases, diseases of genomic
imprinting, diseases of dynamic mutations)
5. Genetic diseases of somatic cells
 Clinical classification of hereditary
diseases

According to the systemic and organ

principle: neuromuscular, cardiovascular,
mental, etc.
By type of metabolic disorder:
hereditary metabolic diseases of
carbohydrates, amino acids, lipids, purines,
pyrimidines, etc.
 Mutations Classification

By nature of genome changes

         Genomic - changes in the number of sets of
chromosomes
         Chromosomal - changes in the structure of
chromosomes (chromosomal rearrangements)
         Gene - local changes in the DNA sequence
By manifestation in heterozygote
        Dominant
        Recessive
According to the conditions of occurrence
        Spontaneous
        Induced
Possible inheritance
       In generative tissues (in germ cells)
       Somatic (in somatic cells)
 Monogenic diseases

• Gene diseases are diseases caused by

gene mutations.
• Gene mutations - changes in the sequence
of nucleotides in a specific region of a DNA
molecule.
• Gene mutations are transmitted from
generation to generation in accordance with
Mendel laws.
• Monogenic diseases are diseases caused
by gene mutations in one gene.
 Classification of gene mutations

• Point mutations (replacement of one pair of

nitrogenous bases):

• Transition - one purine base is replaced by another

(adenine to guanine or vice versa), or a similar
replacement of pyrimidine bases occurs (thymine
with cytosine).

• Transversion - a purine base is replaced by a

pyrimidine base or vice versa.
• Deletions
• Insertions
• Inversions
 Classification of gene mutations
depending on the nature of changes in
protein biosynthesis
• Missense mutations
• Nonsense mutations
• Silent mutations
• Frameshift mutations
• Splice site mutations
• Dynamic mutations
• Regulatory mutations
 Point mutations in DNA can lead to missense
mutations, silent mutations and nonsense mutations at
the protein level

Missense mutation - Silent mutation - a nucleotide

nucleotide substitution leading replacement that does not lead to a
to amino acid substitution in the replacement of the amino acid in
protein the protein
 NONSENSE
MUTATION
point mutation, which leads to
the replacement of the amino
acid codon with a stop codon,
which, in turn, leads to
premature termination of
translation
 Insertions

Normal Mutation

DNA CTG TTG GTC DNA CTG TTG A GTC

mRNA GAC AAC СAG mRNA GAC AAC TCA
protein лей фен вал
Protein лей фен сер

Deletions
Normal Мutation
DNA CTG TTG GTC DNA CTG GTC
mRNA GAC AAC СAG mRNA GAC CAG
protein лей фен вал protein лей вал
 FRAMESHIFT MUTATIONS

• A frameshift mutation is a
genetic mutation caused by
indels (insertions or
deletions) of a number of
nucleotides in a DNA
sequence that is not
divisible by three.
Inversions
Норма Мутация

ДНК CTG TTG GTC ДНК CTG GTT GTC

мРНК GAC AAC СAG мРНК GAC CAA CAG
Белок лей фен вал Белок лей вал вал

Duplications of whole genes can also cause

disease. For example, amyotrophy of Charcot-
Marie-Tooth (a disease of the peripheral nervous
system accompanied by progressive atrophy of the
muscles of the distal limbs), extensive duplication
of chromosome 17 is often found, which includes
the PMP22 gene encoding the peripheral protein
myelin
 Dynamic mutations
- Dynamic mutation is the process by which
certain naturally occurring polymorphic
DNA repeat sequences expand and result
in human disease or fragile sites on
chromosomes

Microsatellite repeats expansion

 Regulatory mutation is a mutation that affects
the regulatory sequences of a gene and leads
to a change in its expression level.

Splice site mutation is a genetic alteration in the DNA

sequence that occurs at the boundary of an exon and an intron
(splice site). This change can disrupt RNA splicing resulting in
the loss of exons or the inclusion of introns and an altered
protein-coding sequence. Also called splice-site variant..
 The development of gene diseases is based
on the following effects of mutant alleles:
• Complete or partial loss of function - cessation of
protein synthesis or a decrease in enzymatic activity
• Quantitative changes (excessive or insufficient
synthesis) of mRNA and the corresponding primary
protein products.
At the level of organism, gene mutations alter the
phenotype of an individual.
Phenotypic signs that medical genetics deal with are
hereditary diseases and symptoms of hereditary
diseases.
 Catalog of hereditary diseases

• In 1966, the first edition of the book of

Professor Victor McKusick,
“Mendelian inheritance in man.
Catalog of autosomal dominant,
autosomal recessive and X-linked
phenotypes”. He collected information
about various states of normal and
pathological signs in humans that
show Mendelian inheritance.
• Since 1994, the paper version of the
catalog has not been published; it
exists in a constantly replenished
online version.

Professor Victor McKusick

профессор генетики и
медицины Университета
Дж.Хопкинса (США)
Online Mendelian Inheritance in Man (OMIM)
OMIM database"
http://www.ncbi.nlm.nih.gov/
 Database statistic OMIM up to 20.03.2019

Type of inheritance autosomal Х-linked Y-linked mitochond. Total

Gene description  * 15,041 728 49 35 15,853

Gene and phenotype, 75 0 0 2 77

combined  +

Phenotype description, 4,844 324 4 31 5,203

molecular basis
known  #
Phenotype description 1,455 123 5 0 1,583
or locus, molecular
basis unknown  %
Other, mainly 1,661 106 2 0 1,769
phenotypes with
suspected mendelian
basis
ИТОГО 23,076 1,281 60 68 24,485
 Total number of identified mutations and
genes
(HGMD Professional release 2017.2)
база данных по мутациям человека
Количество мутаций/генов

Мутации 208 368

Миссенс/нонсенс мутации 94 860
Мутации сайта сплайсинга 15 476
Регуляторные мутации 3 242
Мелкие делеции 25 454
Мелкие инсерции 10 617
Мелкие индели 2 436
Вариации числа повторов 476
Крупные инсерции/дупликации 3 086
Комплексные перестройки 1 638
Крупные делеции 12 833

Гены 8 195
Spectrum of identified mutations

Крупные
Комплексные
инсерции/
Вариации числа перестройки;
дупликации;
повторов; 0,28% 0,98%
Мелкие индели; 1,80% Крупные делеции;
1,44% 7,53%

Мелкие инсерции;
6,25%

Миссенс/ нонсенс
Мелкие делеции; мутации; 55,75%
14,97% Регуляторные Мутации сайта
мутации; 1,91% сплайсинга; 9,10%
 > 7000 monogenic
diseases

5% Due to damage 90% develops Type

Mendelian laws
from all to one gene during puberty of inheritance
of inheritance
diseases 1% - after 40-50
years

Autosomal Autosomal X-linked

dominant recessive Y-linked
 Types of inheritance:
1. Autosomal dominant;
2. Autosomal recessive;
3. X-linked recessive;
4. X-linked dominant;
5. Y-linked (Hollandic)
 Autosomal dominant type of
inheritance
• The disease occurs in every generation of the
pedigree (vertical transmission of the disease).
• The ratio of sick and healthy in the pedigree
approaches 1: 1.
• There is no predominant lesion of one or the other
sex.
• The transfer of a pathological symptom can be
carried out from any of the parents, including from
father to son.
• Healthy parents will have healthy children.
• The probability of having a sick child if one of the
parents is sick is 50%.
Pedigree with an autosomal dominant type of
inheritance

Autosomal dominant diseases:

Marfan syndrome, achondroplasia, brachidactyly,
polydactyly, Charcot-Marie type 1 disease
Autosomal recessive type of inheritance

• Patients are not in every generation;

• Parents of the patient are phenotypically healthy,
spouses heterozygosity is detected only after the
birth of a sick child;
• Men and women are equally affected;
• Inheritance is mainly horizontal;
• The risk of disease for the siblings of the affected
child is 25%;
• If one of the parents is sick, children are usually
healthy
 Pedigree with autosomal recessive inheritance

Autosomal recessive diseases:

phenylketonuria, cystic fibrosis, galactosemia, adrenogenital
syndrome, sickle cell anemia
The PKU (phenylalanine
hydroxylase) gene is
located on 12q.24
Galactosemia
X-linked dominant inheritance, sometimes referred to as X-linked
dominance, is a mode of genetic inheritance by which
a dominant gene is carried on the X chromosome. ... X-linked
dominant traits do not necessarily affect males more than females
(unlike X-linked recessive traits).
 Х-linked dominant
• Both men and women are affected, but
woman are affected twice frequently
• Sick women on average pass the
pathological allele to 50% of sons and 50% of
daughters
• A sick man passes the pathological allele to
all daughters and does not pass on to his
sons, since they receive from his father Y
chromosome
• On average, women (they are heterozygous)
have not such severe disease form than
men (they are hemizygous)
 X-linked dominant inheritance pedigree

X-linked dominant inheritance disorders: Vitamin

D-resistant rickets (hereditary
hypophosphatemia)
 X-linked recessive inheritance
type
• Men are mostly affected
• Inheritance is mainly horizontal
• An affected father can pass the pathological gene only to
daughters, but phenotypically they will be healthy
• A female carrier passes a pathological gene to 50% of her
children
• An affected male receives pathological gene only from
mother
• A female carrier can receive a pathological gene from both
the mother and father
• In an affected homozygous woman who received a
pathological gene from both parents, all sons will also be
affected, and all daughters will be heterozygous carriers
• The probability of inheritance is 25% of all children and
50% in boys.
•  
 X-linked recessive inheritance pedigree

Diseases: hemophilia A, hemophilia B, Duchenne-

Becker muscular dystrophy, color blindness
 Y-linked linked inheritance type (hollandic)
1. Affected persons in all generations;
2. Only men get sick;
3. A sick father has all his sons sick;
4. The probability of inheritance in boys is 100%.

Diseases: ichthyosis of the skin, hypertrichosis (fraying of the external auditory

canals and middle phalanges of the fingers), membranes between the toes ...)
Mitochondrial diseases
 Genetic heterogeneity of monogenic diseases

• Locus heterogeneity: mutations in different genes

cause a single clinical syndrome
• Allelic heterogeneity: different mutations of the same
gene lead to the same hereditary disease
• Allelic diseases: different mutations in one gene lead
to the development of various clinical phenotypes that
qualify as independent diseases (disorders in 165
genes are associated with two phenotypes, in 52
genes - with three, in 24 genes - with four, in 19 - with
five).
• Polyphenia: the same mutation in a gene can cause
different clinical phenotypes (Pfeiffer and Cruson
syndromes, FGFR2 gene)
 Locus heterogeneity of monogenic diseases

• Hereditary motor-sensory neuropathies 30 genes

• Autosomal dominant ataxia

25 genes
• Hereditary spastic paraplegia
22 genes
• Hereditary Dystonia
15 genes
• Autosomal Recessive Muscular Dystrophy
12 genes
•   Parkinson's disease
12 genes
•   Polyneuropathy Degerin-Sott
4 genes
•   Retinitis pigmentosa
24 genes
 Allele heterogeneity of hereditary diseases

•It is characteristic for almost all monogenic hereditary

diseases.
•Various mutations in the same gene result in diseases with
similar clinical symptoms, with slight variations in the degree
of generalization of the process and the severity of the disease
course.
•Phenotypic diversity is due to:
•different mechanism of action of mutations on the translation
processes of a protein product;
•the presence of one or more modifier genes that regulate the
expression of the mutant gene;
•differences in the degree of protein dysfunction during
mutations that alter the amino acid sequence of individual
domains.
 PHENOTYPIC VARIABILITY

The same mutations can lead to different phenotypic

manifestations due to the influence of epigenetic,
environmental and random factors.
Mutations that affect regulatory sequences or mRNA
stability can modulate changes in expression levels,
leading to phenotypic changes.
Most phenotypic variants in Mendelian diseases are the
result of the interaction of several genes.
The main reason that they are referred to as Mendelian
is that the main phenotype can be associated with
mutations at one locus.
Modifier genes (thalassemia, sickle cell anemia, cystic
fibrosis, muscle atrophy).
 Cystic Fibrosis Modifier Genes

Scheme of the influence of additional factors, such as modifier genes (MBL, HLA,
TNFA, TGFB1), genetic background, epigenetic factors and environmental factors,
on the development of cystic fibrosis
 ETHNIC HETEROGENEITY

• ON THE PREVALENCE OF HEREDITARY

DISEASES

• ON FREQUENCY AND SPECTRUM OF

MUTATIONS IN GENES

• ON THE DISTRIBUTION OF
FREQUENCIES OF POLYMORPHISMS
LINKED TO THE GENES OF
HEREDITARY DISEASES
 Signs of clinical manifestations of
hereditary pathology
• The family nature of the disease
• Chronic progressive recurrent course
• Specific Symptoms of Hereditary Diseases
• Multiple pathological changes in organs and
systems
• Congenital nature of the disease
• Resistance to the most common types of
therapy
Diagnosis of hereditary diseases

• Genealogy Data Analysis

• Clinical examination
• Paraclinical examination
• Biochemical diagnostics
• Molecular diagnostics
 Lessons from monogenic
diseases investigations
• New genetic mechanisms:
homogeneous disomy, genomic
imprinting, epistatic interactions,
CNV changes
• Phenotypic variability (cystic fibrosis,
congenital deafness ...)
• Modifier genes (thalassemia, sickle
cell anemia, cystic fibrosis, muscle
atrophy)
 Lessons from monogenic
diseases investigations

• Most phenotypic variants in Mendelian

diseases are the result of the interaction of
several genes.
•      The main reason that they are referred
to Mendelian diseases is that the main
phenotype can be associated with
mutations at one locus.
 Rare (ORPHAN) diseases

Rare (ORPHAN)diseases are often serious, life-threatening and

debilitating group of disorders. Nowadays, there are approximately 8,000
rare diseases and it is estimated that 350 million people are affected by
these conditions worldwide.
Unfortunately, rare diseases are quite complex and chronic, only a small
number of these diseases can be relevantly diagnosed and treated, and
lifelong treatment is often required.
WHO: defines orphan/rare disease as
«all pathological conditions that affect
0.65-1%out of every 1000 inhabitants»

The European Organization: defines as rare one with a

prevalence of
5: 10 000 Europeans
• USA: Orphan Drug Act of 1983 - Diseases or
conditions affecting less than 200,000 people, or
about 1 in 1,500 people.
• Japan: Diseases affecting less than 50,000
patients, or about 1 in 2,500.
• Europe: EURORDIS - diseases affecting less than
1 in 2,000 people in a population.
• In Russia rare (orphan) diseases are diseases that
have a prevalence of no more than 10 cases per
100 thousand population.
 Orphanic (rare) diseases are characterized by 3
signs:
rarely found in the population (statistically rare - 1:
10000 of the population);
are chronic life-threatening or causing chronical
debilitating diseases;
require a specific agent for their treatment (orphan
drugs).
 COMMON
CHARACTERISTICS OF
RARE DISEASES

Rare diseases are severe to very severe, chronic, often

degenerative and life threatening

Disabling the quality of life of rare disease patients is often

compromised by lack or loss of autonomy

Highly painful in terms of psychosocial burden: the suffering of

rare disease patients and their family is aggravated by
psychological despair, lack of therapeutic hope, absence of
practical support for everyday life
 ORPHAN DISEASES

• exist in all classes of diseases,

Totally are divided into:
• Genetically determined forms - 80%
• Other (cardiological, infectious, endocrine,
hematological, etc.) forms - 20%
"LOAD“ of
RARE DISEASES

• 65% - severe disabling course;

• 50% - poor prognosis for life;
• 35% - the cause of death during the 1st year
of life;
• 10% - the cause of death within 1-5 years;
• 12% - the cause of death within 5-15 years;
• Every fifth patient has a chronic pain
syndrome.
Manifestation of rare
diseases

• Manifestation at any age (affect both children and

adults)
• Over 2/3 of rare diseases manifest at in early
childhood
• The pharmaceutical industries are reticent to invest in
rare diseases treatment
Diagnosis of rare diseases

• Accurate diagnosis is a critical moment in rare

diseases;
• Diagnosis difficulties:
• Rarity in the population;
• Genetic heterogeneity;
• Clinical polymorphism, the presence of numerous
"masks" of hereditary diseases;
• Doctors make errors in diagnoses.
• The consequences of incorrect diagnosis (late
treatment, progressive dysfunction, death).
Diagnosis of rare diseases

• clinical and genealogical (pedigree);

• mass screening of newborns for hereditary diseases;
• selective screening programs;
• methods of analytical biochemistry, chromatography-mass
spectrometry, fluorometry, fluorescence analysis;
• cytogenetic, molecular cytogenetic (FISH method - in situ
fluorescence hybridization), SKY method - spectral
karyotyping method;
• molecular genetic:
• polymerase chain reaction (PCR),
• CGH - method - a method of comparative genomic
hybridization (microarray of DNA probes),
• genetic microchip technology,
• NGS sequencing;
• Other
Treatment of rare diseases

• Pathogenetic treatment = clarity of diagnosis is

necessary
• Orphan drugs are drugs for the treatment,
diagnosis, or prevention of rare diseases.
• Most of these drugs are classified as expensive
and are provided at the expense of the federal or
regional budget.
• In most cases, life-long therapy is necessary
Treatment of rare diseases

In total, there are 7-8 thousand orphan diseases, and drugs

are created only for 300
Treatment of rare diseases

1. gene therapy - the radical elimination of a genetic

defect for treatment the patient himself (when
transferring cloned genes to somatic cells),
and the prevention of disease in his offspring (when
transferring genes to germ cells).

2. pathogenetic (substitution, corrective) and

symptomatic therapy - attempts to normalize disorders
without directly affecting the underlying genetic defect
3. diet therapy with the exception of the intake with food
of those substances whose concentration in the blood
is increased (PKU, homocystiuria, tyrosinemia, maple
syrup urine disease, etc.),
4. Replacement therapy (hormones, enzymes)
5. surgical correction of congenital malformations
Pathogenetic therapy

Metabolic correction
Dietary restriction (phenylalanine for PKU, galactose or fructose for
galactosemia)
Additional intake of active substances (biotin for biotinidase deficiency)
Chelation and enhanced excretion (copper binding in Wilson's disease,
hemodialysis in hyperammonemia)
 Metabolic inhibitors (statins for familial hypercholesterolemia)
Enzyme function correction
Increase in residual enzyme activity (coenzyme)
- “Pharmacological chaperones”
Replacement therapy
- Enzyme replacement therapy
- Product replacement therapy
Organ transplantation and symptomatic therapy
- Liver (tyrosinemia)
- Kidneys (Fabry disease)
Gene therapy
- HSC transplantation
- Genome editing
 Human glycogen storage diseases
Glycogenosis

Type I - von Girke's disease (hepatorenal glycogenosis). Glucose 6-

phosphatase deficiency (G6PC gene).
Type II - Pompe disease. α-1,4-glucosidase (GAA gene) deficiency.
Type III - Forbes-Corey disease (limit-dextrinosis). Amylo-1,6-
glucosidase deficiency (AGL gene).
IV type - Andersen's disease (amylopectinosis). Amylo-1,4,1,6-
transglucosidase deficiency (GBE1 gene).
V type - MacArdle's disease. Myophosphorylase Deficiency (PYGM
gene).
VІ - Hers disease. Hepatic phosphorylase deficiency (PYG1 gene).
VII Fanconi-Bickel syndrome. Deficiency of glucose transporter
protein (SLC2A2 gene).
 Human glycogen storage diseases

Type II - Pompe disease. α-1,4-glucosidase (GAA)

deficiency.

Pompe disease is an inherited disorder caused by the buildup

of a complex sugar called glycogen in the body's cells. The
accumulation of glycogen in certain organs and tissues,
especially muscles, impairs their ability to function normally.

Treatment: lifelong replacement therapy with recombinant

human acidic α-glucosidase (alglucosidase alpha)

reduces the risk of death by 99%,

reduces the risk of death or the need for invasive

ventilation by 92%
 Pompe disease

Researchers have described three types of Pompe disease,

which differ in severity and the age at which they appear.
These types are known as classic infantile-onset, non-
classic infantile-onset, and late-onset.
The classic form of infantile-onset Pompe disease begins
within a few months of birth. Infants with this disorder
typically experience muscle weakness (myopathy), poor
muscle tone (hypotonia), an enlarged liver (hepatomegaly),
and heart defects. Affected infants may also fail to gain
weight and grow at the expected rate (failure to thrive) and
have breathing problems. If untreated, this form of Pompe
disease leads to death from heart failure in the first year of
life.
 Pompe disease

The non-classic form of infantile-onset Pompe disease usually

appears by age 1. It is characterized by delayed motor skills
(such as rolling over and sitting) and progressive muscle
weakness. The heart may be abnormally large (cardiomegaly),
but affected individuals usually do not experience heart failure.
The muscle weakness in this disorder leads to serious breathing
problems, and most children with non-classic infantile-
onset Pompe disease live only into early childhood.
The late-onset type of Pompe disease may not become
apparent until later in childhood, adolescence, or adulthood.
Late-onset Pompe disease is usually milder than the infantile-
onset forms of this disorder and is less likely to involve the heart.
Most individuals with late-onset Pompe disease experience
progressive muscle weakness, especially in the legs and the
trunk, including the muscles that control breathing. As the
disorder progresses, breathing problems can lead to respiratory
failure.
 Lysosomal storage disease

• Diseases, the basis of the pathology of which is a violation of

the functions of lysosomal enzymes
• Mostly inherited autosomal recessively, with the exception of,
for example, Hunter and Fabry diseases
• Total > 50
• Divided into subclasses depending on which molecules
accumulate
Groups Diseases
Sphingolipidoses Nimann-Peak disease, Fabry disease, disease
Crabbe, Gaucher disease, Tay-Sachs disease,
Metachromatic leukodystrophy
Mucopolysaccharidosis Type I (Gurler, Scheier), II (Hunter), III
(Sanfilippo), IV (Morkio), VI (Marto Lamy), VII (Sly) and
XI
Mucolipidoses Тypes I-IV
 Nyman-Peak Disease
Genes Types Biochemical alterations
SMPD1 А,В Sphingomyelin phosphodiesterase 1 defect (impaired
sphingomyelin breakdown)
NPC1 или NPC2 C Defective membrane transporter proteins

Autosomal recessive inheritance

Incidence - from 1: 40,000 (type A among Ashkenazi
Jews) to 1: 250,000 and less
Clinical picture
Hepatosplenomegaly
Accumulation of sphingomyelin in the central nervous
system: ataxia, dystonia, impaired speech and
swallowing, impaired intelligence, sleep disturbances
Type A: classic infantile (85% of cases)
hepatosplenomegaly, total CNS damage, life expectancy
<18 months
Type B: visceral - without damage to the central nervous
system, mortality <20%
Type C: subacute / juvenile
 Nyman-Peak Disease

Pathogenetic factors - potential therapeutic targets

CNS myelin loss
Sphingomyelin accumulation
Experimental Therapy Options
Arimoclomol (CytRx corporation): type C - molecular chaperone activator
Arimoclomol (INN; originally codenamed BRX-345, which is a citrate salt formulation of BRX-220) is an
experimental drug developed by CytRx Corporation. Arimoclomol is believed to function by stimulating a
normal cellular protein repair pathway through the activation of molecular chaperones. Since damaged
proteins, called aggregates, are thought to play a role in many diseases, CytRx believes that arimoclomol
could treat a broad range of diseases.

Miglustat: inhibits synthase

glucosylceramide, which leads to a decrease in the
number of glycosphingolipids in glial cells and neurons

HPbCD (2-hydroxypropyl-β-cyclodextrin) (Vtesse Inc):

improves cholesterol metabolism, amyloid β
aggregation inhibitor β
 FABRY DISEASE

• X-linked recessive inheritance α-

• Prevalence from 1 in 40,000 to 1 in 500,000 newborns галактозидаза
• Mutations of the GLA gene that controls the structure А
•  α-galactosidase A → accumulation of ganglioside α-galactosidase A
globotriaosylceramide (CD77, Gb3)
• Symptoms are nonspecific
• Pain (non-localized or only in the limbs or only in the
digestive tract)
• Renal failure and proteinuria
• Heart failure and restrictive cardiomyopathy
• Skin manifestations: angiokeratomas,
• sweating disorders (anhidrosis or
• hyperhidrosis)

• Diagnosis - determination of alpha galactosidase

activity,
• quantification of sphingolipids Lyso-GB3, Lyso-GL3
• Pilot mass screening programs in Europe using tandem
mass spectrometry: 1: 3000 newborn boys (Italy)
 FABRY DISEASE
• mutation in alpha-galactosidase A (a-GAL A) gene
causes a poor breakdown of lipids. This leads to a
harmful buildup of lipids – specifically
globotriaosylceramide (GL-3) – in the cardiovascular
system, autonomic nervous system, kidneys, and eyes.
• There are several lipid storage disorders. Fabry disease
is the only X-linked, or inherited, one.
• The mutated gene is carried in the mother’s X-
chromosome, leading to a 50 percent chance she will
pass it on to her sons, and a 50 percent risk that her
daughters will be carriers.
 FABRY DISEASE

• Treatment: symptomatic therapy (painkillers, anticonvulsants) + enzyme

replacement therapy (Repagal, Fabrazim)
• Agalsidase alpha and agalsidase beta
• Replacement therapy:
• reduced the severity of neuropathic pain, in
• regression of left ventricular hypertrophy and stabilization of renal function
• delayed the development of renal and cardiovascular failure
 FABRY DISEASE
• The optimal timing of prescribing replacement therapy is not defined
• For men with Fabry disease, replacement therapy is indicated immediately after
establishing a diagnosis. In boys with asymptomatic Fabry disease, treatment may
be started at the age of 10-13 years.
• In women, indications for treatment are expressed symptoms or signs of progressive
damage to target organs, including chronic neuropathic pain in the hands and feet,
resistant to standard therapy, persistent proteinuria, decreased glomerular filtration rate
• Criteria of inappropriateness of appointment:
• pregnancy and lactation;
• the presence of another life-threatening disease in which the prognosis is unlikely to be
improved by enzyme replacement therapy ;
• patients with Fabry disease who have serious complications (e.g.
• severe stroke, resuscitation patients).
• The prognosis of life with full monitoring of the disease and compliance with medical
recommendations is favorable. Life expectancy is not significantly different from
healthy individuals
 Gaucher Disease

• Types of Gaucher Disease

• Scientists divide Gaucher disease into 3 different types based on
presence or absence of early onset brain involvement, including:
• Gaucher disease type 1: Gaucher disease type 1 is the most
common form of the disease in western countries, making up
roughly 95 percent of patients there. Symptoms include spleen and
liver enlargement, bone problems and fatigue. Brain development is
normal. Treatable
• Gaucher disease type 2: This type of Gaucher disease is rare and
involves severe neurological (brain stem) abnormalities. It is usually
fatal within the first 2 years, and it is currently untreatable because
of the severe, irreversible brain damage.
• Gaucher disease type 3: Gaucher disease type 3 has a severity
between types 1 and 2, causing the same symptoms as type 1 plus
some neurological involvement. While patients typically have a
shortened lifespan, some can live into their 50s with treatment.
 Gaucher Disease
• Inherited in an autosomal recessive manner
• Lysosomal enzyme defect β-D-glucosidase or β-glucocerebrosidase

• Congenital insufficiency of this enzyme leads to the accumulation of glucocerebroside in

• cells of the reticuloendothelial system, especially in the liver, spleen and bone marrow.

• 3 clinical types
• Type 1 (non-neuropathic): 1: 50,000 newborns
• Type 2 (Neuronopathic infantile): 1: 100,000 newborns
• Type 3 (Subacute neuronopathic juvenile): 1: 100,000 newborns
• Among Ashkenazi Jews 1: 850, the frequency of carriage of the disease 1:12
• Pilot mass screening programs in Europe using tandem mass spectrometry: 1: 17600 newborns!

• The main clinical manifestations (type 1)

• Hepatosplenomegaly
• Asthenic syndrome
• Hemorrhagic syndrome
• Bone pain, including bone crises
• Impaired joint mobility due to aseptic necrosis
• Pathological fractures
• Lag in physical and sexual development
 Gaucher Disease

Наследуется по аутосомно-рецессивному типу

Дефект лизосомного фермента β-D-глюкозидазы или β-глюкоцереброзидазы
Врожденная недостаточность этого фермента ведет к накоплению глюкоцереброзида в
клетках ретикулоэндотелиальной системы, особенно в печени, селезенке и костном мозге.

3 клинических типа
-Тип 1 (Ненейропатический): 1:50000 новорожденных
-Тип 2 (Нейронопатический инфантильный): 1:100 000 новорожденных
-Тип 3 (Подострый нейронопатический ювенильный): 1:100 000 новорожденных
Среди евреев ашкенази 1:850, частота носительства заболевания 1:12
Пилотные программы массового скрининга в Европе с применением тандемной масс-
спектрометрии: 1:17600 новорожденных!

Основные клинические проявления (тип 1)

•Гепатоспленомегалия
•Астенический синдром
•Геморрагический синдром
•Костные боли, в том числе костные кризы
•Нарушение подвижности в суставах, обусловленное асептическим некрозом
•Патологические переломы
•Отставание в физическом и половом развитии
Gaucher Disease
Gaucher Disease
Gaucher Disease
 Gaucher Disease

Groups Drug name Trading Manufacturer The In Russia

name beginning
of therapy
in the world
Enzymes Immiglucerase Церезим Джензайм 1995 +

Velaglucerase alfa ВПРИВ Шайер 2010 2013

Taliglucerase alfa Elelyso Пфайзер 2012 no

Small Miglustat Завеска Актелион 2002 2009

molecules
Eliglustat Cerdelga Джензайм 2014 no

Alglucerase (since 1991, now not used) - placental enzyme

Imiglucerase - is synthesized by a cell line derived from the ovaries of Chinese
hamsters; Velaglucerase alpha - is produced by the human fibroblast cell line HT-
1080.
Taliglucerase alfa - produced by modified carrot cells

In clinical trials in Russia:

Imiglucerase (Glurazim): Generium Eliglustat: IIIb phase (until 2019)
 Mucopolysaccharidosis
• Mucopolysaccharidosis (MPS) involves defective activity of the
lysosomal enzymes that degrade mucopolysaccharides
(glycosaminoglycans [GAGs] attached to a link protein with a
hyaluronic acid core) into smaller components. The resulting
incomplete degradation process leads to abnormal accumulation of
heparan sulfate, dermatan sulfate, and keratan sulfate, and the
abnormal accumulation of these compunds interferes with cell
function.
• Different forms of MPS were described separately throughout the
20th century. Their clinical presentations vary, depending on the
type of enzyme defect and the glycoprotein accumulated
•
Mucopolysaccharidosis
Mucopolysaccharidosis
Mucopolysaccharidosis
Mucopolysaccharidoses

Type Disease Enzyme deficiency

Type I (H, S, H/S) Gurler α-L-iduronidase
Gurler Sheye
Sheye
(ex. V)
Type II Hunter Iduronate sulfatase
Type III (А, В, С, D) Sanfilippo • Heparan sulfamidase
• N-acetylglucosaminidase
• Heparan-α-glucosaminide-N-
• acyltransferase
• N-acetylglucosamine-6-sulfatase
Type IV (A, В) Morquio Galactose-6-sulfate sulfatase β-
galactosidase
Type VI Maroteaux-Lamy N-acetylgalactosamine-4-sulfatase
TypeVII Slai β-glucuronidase
Type IX Natowicz Hyaluronidase
Mucopolysaccharidoses

Гурлер-подобный Моркио-подобный
Рост низкий с Рост - диспропорциональная
диспропорциональным карликовость
строением скелета
Mucopolysaccharidoses

Гурлер-подобный Моркио-подобный
Черты лица грубые, Черты лица грубоватые,
характерные неспецифичные
Интеллект как правило, снижен Интеллект как правило, сохранен
 Mucopolysaccharidoses
Clinical polymorphism: Hurler
 Mucopolysaccharidoses
ХАНТЕР
МОРКИО
Mucopolysaccharidoses
Mucopolysaccharidoses
Clinical Polymorphism: Hunter
Mucopolysaccharidoses
Clinical Polymorphism: Hunter
Mucopolysaccharidoses

Morquio-like
Gurler-like
Bone deformities: keeled chest
Bone deformities:
Joints: interphalangeal
dysostosis, kyphoscoliosis,
hypermobility and stiffness of
funnel chest deformity
large joints, increased joint
Joints: stiffness, joint volume and hallux valgus
contracture
 Mucopolysaccharidoses

Morquio-like
Gurler-like Pathology of
Pathology of internal organs: internal organs:
hepatosplenomegaly, hernia, heart Hernia and
valve insufficiency, hepatosplenomegal
myocardial hypertrophy, y are not
sinusobronchopathy characteristic, other
changes - as with
Hurler-like
phenotype
 Mucopolysaccharidoses:
treatment

Type Disease Drugs In Russia

Type I (H, S, H/S) Gurler Laronidase since 2008
Gurler Sheye (Aldurazim), jensheim
Sheye
(ex. V)
Type II Hunter Idursulfase since 2008
(Elapraz), Scheyer
Idursulfase beta since 2018
(Hunterase), Green Cross

Type IV (A, В) Morquio Elosulfase Alpha

(Wimizim), Biomarin
Type VI Maroteaux-Lamy Halsulfase (Naglazim), since 2009
Biomarin
Thank you for your
attention!