HEREDITARY

METABOLIC
DISORDERS
LECTURER: MEERIM KURMANALIEVA
SUBJECT: MEDICAL GENETICS
 LECTURE CONTENT
• GENERAL CHARACTERISTICS
• BIOCHEMICAL CLASSIFICATION
• CLINICAL CLASSIFICATION
• PHENYLKETONURIA
• GAUCHER DISEASE (SPHINGOLIPIDOSIS)
• MUCOPOLYSACCHARIDOSIS
 DEFINITION

• HEREDITARY METABOLIC DISORDERS (HMD) INCLUDE A LARGE GROUP OF HEREDITARY

DISEASES AFFECTING METABOLIC DISORDERS (METABOLISM). SUCH DISORDERS CONSTITUTE A
SIGNIFICANT PART OF THE GROUP OF METABOLIC DISORDERS (METABOLIC DISEASES).
• AMONG HEREDITARY HUMAN DISEASES, HEREDITARY METABOLIC DISEASES OCCUPY ONE OF
THE MOST SIGNIFICANT PLACES. CURRENTLY THIS GROUP INCLUDES ABOUT 700 DIFFERENT
DISEASES.
 GENERAL CHARACTERISTICS OF MONOGENIC
HEREDITARY METABOLIC DISEASES:
• 1. THEY ARE INNATE IN NATURE;
• 2. MANIFEST AT ANY AGE;
• 3. THEY ARE MANIFESTED BY CERTAIN, OFTEN PROGRESSIVE CLINICAL SYMPTOMS;
• 4. ACCOMPANIED BY GROSS VIOLATIONS OF HUMAN LIFE;
• 5. ACCOMPANIED BY VARYING DEGREES OF MENTAL RETARDATION;
 GENERAL CHARACTERISTICS OF MONOGENIC
HEREDITARY METABOLIC DISEASES:
• 6. TIME-CONSUMING AND EXPENSIVE TREATMENT;
• 7. HAVE A HIGH RISK OF TRANSMISSION TO OFFSPRING;
• 8. IN CASES OF ACCURATE DIAGNOSIS AND AVAILABILITY OF DETAILED INFORMATION ABOUT
THE TYPE OF MUTATION AND ITS CLINICAL (BIOCHEMICAL) MANIFESTATIONS PRENATAL
DIAGNOSIS IS INDICATED;
• 9. IN CASES OF DEVELOPMENT OF EFFECTIVE THERAPY, THEY ARE SUBJECT TO PRECLINICAL
DETECTION AND TREATMENT.
 BIOCHEMICAL CLASSIFICATION
1. DISEASES OF AMINO ACID METABOLISM;
2. DISEASES OF CARBOHYDRATE METABOLISM;
3. DISEASES OF ORGANIC ACID METABOLISM;
4. DISEASES OF FATTY ACID METABOLISM;
5. DISEASES OF PURINE AND PYRIMIDINE METABOLISM;
6. DISEASES OF CHOLESTEROL METABOLISM;
7. HEME AND PORPHYRIN METABOLISM DISEASES;
8. DISEASES OF METAL METABOLISM;
9. DISEASES OF VITAMIN METABOLISM;
10. DISEASES OF CELLULAR ORGANELLES: LYSOSOMAL, PEROXISOMAL, MITOCHONDRIAL;
11. UREA CYCLE DISORDERS.
 CLINICAL CLASSIFICATION
IMD group Clinical features Examples of
diseases
Violations of The symptoms Lysosomal,
the synthesis are constant, peroxisomal
and decay of progressive, do diseases
biomacromolec not depend on
ules intercurrent
diseases and
are not related
to nutritional
 CLINICAL CLASSIFICATION
IMD group Clinical features Examples of
diseases
Intoxicatio Acute intoxication: Disorders of
n-type vomiting, lethargy, the
diseases coma, liver failure, metabolism of
thromboembolism
Chronic intoxication:
amino acids,
progressive delayed organic acids,
psycho-motor the urea cycle
development,
cardiomyopathy.
Acidosis, ketosis,
 CLINICAL CLASSIFICATION
IMD group Clinical features Examples of
diseases

Violations of Muscular Mitochondrial

energy hypotension, diseases, fatty
generation and cardiomyopathy, acid
delayed psycho-
utilization motor
metabolism
development, diseases,
fatty liver glycogenoses
dystrophy. Lactic
acidosis,
 INHERITANCE OF METABOLIC DISEASES

1. AUTOSOMAL RECESSIVE TYPE OF INHERITANCE;

2. AUTOSOMAL DOMINANT TYPE OF INHERITANCE;
3. X-LINKED RECESSIVE TYPE OF INHERITANCE (MPS II (HUNTER’S
DISEASE);
4. MITOCHONDRIAL (MATERNAL) INHERITANCE.
 VARIANTS OF CLINICAL MANIFESTATION OF HMD

1. ACUTE SEVERE DISORDERS IN THE NEONATAL PERIOD;

2. LATE-ONSET ACUTE OR RECURRING SYMPTOMS;
3. CHRONIC PROGRESSIVE SYSTEMIC DISORDERS;
4. SPECIFIC PERMANENT SIGNS INDICATING CERTAIN NOSOLOGICAL
FORMS.
 DISEASES OF AMINO ACID METABOLISM

PHENYLKETONURIA
SYNONYMS:
• CLASSICAL PHENYLKETONURIA
• HYPERPHENYLALANINEMIA
• PHENYLALANINE HYDROXYLASE DEFICIENCY
• PHENYLALANINEMIA
• PKU
 PHENYLKETONURIA

• PHENYLKETONURIA IS A HEREDITARY DISEASE OF THE GROUP OF FERMENTOPATHIES

ASSOCIATED WITH A VIOLATION OF THE METABOLISM OF AMINO ACIDS, MAINLY
PHENYLALANINE. NON-COMPLIANCE WITH A LOW-PROTEIN DIET IS ACCOMPANIED BY THE
ACCUMULATION OF PHENYLALANINE AND ITS TOXIC PRODUCTS, WHICH LEADS TO SEVERE
DAMAGE TO THE CENTRAL NERVOUS SYSTEM, MANIFESTED, IN PARTICULAR, IN THE FORM OF
IMPAIRED MENTAL DEVELOPMENT (PHENYLPYRUVIC OLIGOPHRENIA). ONE OF THE FEW
HEREDITARY DISEASES THAT CAN BE SUCCESSFULLY TREATED.
 CAUSE AND PATHOLOGY

• THE DISEASE IS INHERITED IN AN AUTOSOMAL RECESSIVE TYPE.

• THE PAH GENE IS LOCATED ON CHROMOSOME 12.
• IN MOST CASES, THE DISEASE IS ASSOCIATED WITH A SHARP DECREASE OR COMPLETE
ABSENCE OF ACTIVITY OF THE LIVER ENZYME PHENYLALANINE-4-HYDROXYLASE, WHICH
NORMALLY CATALYZES THE CONVERSION OF PHENYLALANINE TO TYROSINE.
• UP TO 1% OF CASES OF PHENYLKETONURIA ARE REPRESENTED BY ATYPICAL FORMS
ASSOCIATED WITH MUTATIONS IN OTHER GENES RESPONSIBLE FOR ENCODING ENZYMES THAT
PROVIDE SYNTHESIS OF THE PHENYLALANINE HYDROXYLASE COFACTOR —
TETRAHYDROBIOPTERIN (BH4).
 HISTORY

• THE DISCOVERY OF PHENYLKETONURIA IS ASSOCIATED WITH THE NAME OF

THE NORWEGIAN PHYSICIAN IVAR ASBJORN FELLING, WHO DESCRIBED
HYPERPHENYLALANINEMIA ASSOCIATED WITH MENTAL RETARDATION IN 1934.
IN NORWAY, THE DISEASE IS ALSO KNOWN AS "FELLING'S DISEASE" (NORV.
FØLLINGS SYKDOM) IN HONOR OF THE DISCOVERER.
 EPIDEMIOLOGY

• HE AVERAGE NUMBER OF NEW CASES OF PKU VARIES IN DIFFERENT HUMAN

POPULATIONS. UNITED STATES CAUCASIANS ARE AFFECTED AT A RATE OF 1 IN
10,000. TURKEY HAS THE HIGHEST DOCUMENTED RATE IN THE WORLD, WITH 1
IN 2,600 BIRTHS, WHILE COUNTRIES SUCH AS FINLAND AND JAPAN HAVE
EXTREMELY LOW RATES WITH FEWER THAN ONE CASE OF PKU IN 100,000
BIRTHS. A 1987 STUDY FROM SLOVAKIA REPORTS A ROMA POPULATION WITH
AN EXTREMELY HIGH INCIDENCE OF PKU (ONE CASE IN 40 BIRTHS) DUE TO
EXTENSIVE INBREEDING. IT IS THE MOST COMMON AMINO ACID METABOLIC
PROBLEM IN THE UNITED KINGDOM.
 SYMPTOMS OF PHENYLKETONURIA
• PKU SYMPTOMS CAN RANGE FROM MILD TO SEVERE.
• THE MOST SEVERE FORM OF THIS DISORDER IS KNOWN AS CLASSIC PKU.
• AN INFANT WITH CLASSIC PKU MAY APPEAR NORMAL FOR THE FIRST FEW MONTHS OF
THEIR LIFE.
• IF THE BABY ISN’T TREATED FOR PKU DURING THIS TIME, THEY’LL START TO DEVELOP
THE FOLLOWING SYMPTOMS:
• SEIZURES;
• TREMORS, OR TREMBLING AND SHAKING;
• STUNTED GROWTH;
• HYPERACTIVITY;
• SKIN CONDITIONS SUCH AS ECZEMA;
• A MUSTY ODOR OF THEIR BREATH, SKIN, OR URINE;
 SYMPTOMS OF PHENYLKETONURIA

• IF PKU ISN’T DIAGNOSED AT BIRTH AND TREATMENT ISN’T STARTED QUICKLY, THE DISORDER
CAN CAUSE:
• IRREVERSIBLE BRAIN DAMAGE AND INTELLECTUAL DISABILITIES WITHIN THE FIRST FEW
MONTHS OF LIFE
• BEHAVIORAL PROBLEMS AND SEIZURES IN OLDER CHILDREN
• A LESS SEVERE FORM OF PKU IS CALLED VARIANT PKU OR NON-PKU HYPERPHENYLALANINEMIA.
THIS OCCURS WHEN THE BABY HAS TOO MUCH PHENYLALANINE IN THEIR BODY. INFANTS WITH
THIS FORM OF THE DISORDER MAY HAVE ONLY MILD SYMPTOMS, BUT THEY’LL NEED TO
FOLLOW A SPECIAL DIET TO PREVENT INTELLECTUAL DISABILITIES.
• ONCE A SPECIFIC DIET AND OTHER NECESSARY TREATMENTS ARE STARTED, SYMPTOMS START
TO DIMINISH. PEOPLE WITH PKU WHO PROPERLY MANAGE THEIR DIET USUALLY DON’T SHOW
ANY SYMPTOMS.
 MATERNAL PKU

• THE DISEASE IS AN EMBRYOPHETOPATHY: A SYNDROME OF MENTAL RETARDATION AND

CONGENITAL ANOMALIES AS A RESULT OF THE EFFECT ON THE FETUS OF A HIGH LEVEL OF
PHENYLALANINE IN THE BLOOD OF A MOTHER WHO SUFFERS FROM PHENYLKETONURIA;
• CHILDREN HAVE MENTAL RETARDATION, CONGENITAL HYDROCEPHALUS, LOW BIRTH WEIGHT,
HYPOPLASIA OF CERTAIN REGIONS OF THE BRAIN, HEART DEFECTS AND OTHER ORGANS,
MICROANOMALIES OF DEVELOPMENT;
• THE SEVERITY OF CLINICAL MANIFESTATIONS DEPENDS ON THE DEGREE OF INCREASE IN PHE
LEVEL IN THE MOTHER'S BLOOD DURING PREGNANCY.
 NEWBORN SCREENING
• PKU IS COMMONLY INCLUDED IN THE NEWBORN SCREENING PANEL OF MANY COUNTRIES,
WITH VARIED DETECTION TECHNIQUES. MOST BABIES IN DEVELOPED COUNTRIES ARE
SCREENED FOR PKU SOON AFTER BIRTH. SCREENING FOR PKU IS DONE TO DETERMINE THE
CONCENTRATION OF PHE AND THE RATIO OF PHE TO TYROSINE, THE RATIO WILL BE ELEVATED
IN PKU. (GUTRIE TEST)
 TREATMENT

• PKU IS NOT CURABLE. HOWEVER, IF PKU IS DIAGNOSED EARLY ENOUGH, AN AFFECTED

NEWBORN CAN GROW UP WITH NORMAL BRAIN DEVELOPMENT BY MANAGING AND
CONTROLLING PHENYLALANINE LEVELS THROUGH DIET, OR A COMBINATION OF DIET AND
MEDICATION.
• TREATMENT SHOULD BE STARTED NO LATER THAN 3 WEEKS OF THE CHILD'S LIFE. A DIET IN
WHICH IT IS NECESSARY TO EXCLUDE EXCESSIVE INTAKE OF PHENYLALANINE INTO THE CHILD'S
BODY, THE SOURCE OF WHICH IS PROTEIN FOOD. BABY FORMULAS FOR NUTRITION THAT DO
NOT CONTAIN PHE ARE USED. BREAST FEEDING IS CONTRAINDICATED.
 LYSOSOMAL ACCUMULATION DISEASES
• LYSOSOMAL ACCUMULATION DISEASES IS THE COMMON NAME OF A GROUP OF
VERY RARE HEREDITARY DISEASES CAUSED BY A VIOLATION OF THE FUNCTION
OF INTRACELLULAR ORGANELLES OF LYSOSOMES. THESE SINGLE-MEMBRANE
ORGANOIDS ARE PART OF THE ENDOMEMBRANE SYSTEM OF THE CELL AND
SPECIALIZE IN THE INTRACELLULAR CLEAVAGE OF SUBSTANCES: GLYCOGEN,
GLYCOSAMINOGLYCANS, GLYCOPROTEINS AND OTHERS. LYSOSOMAL
ACCUMULATION DISEASES ARE CAUSED BY A GENETICALLY DETERMINED
DEFICIENCY OF LYSOSOME ENZYMES, WHICH LEADS TO THE ACCUMULATION OF
MACROMOLECULES, WHICH ARE THE SUBSTRATE OF THESE ENZYMES, IN
VARIOUS ORGANS AND TISSUES OF THE BODY.
 GAUCHER DISEASE (SPHINGOLIPIDOSIS)
• GAUCHER DISEASE (SPHINGOLIPIDOSIS) IS A HEREDITARY DISEASE, IS THE MOST
COMMON OF LYSOSOMAL ACCUMULATION DISEASES. IT DEVELOPS AS A RESULT
OF INSUFFICIENCY OF THE ENZYME GLUCOCEREBROSIDASE, WHICH LEADS TO
THE ACCUMULATION OF GLUCOCEREBROSIDE IN MANY TISSUES, INCLUDING
THE SPLEEN, LIVER, KIDNEYS, LUNGS, BRAIN AND BONE MARROW. THE DISEASE
IS ASSOCIATED WITH A RECESSIVE MUTATION IN THE GBA GENE LOCATED ON
THE 1ST CHROMOSOME, AND AFFECTS BOTH MEN AND WOMEN. THE DISEASE
IS NAMED AFTER THE FRENCH PHYSICIAN PHILIPPE GAUCHER, WHO FIRST
DESCRIBED IT IN 1882. GAUCHER'S DISEASE IS DIVIDED INTO THREE MAIN
TYPES.
 TYPE I
• GAUCHER DISEASE I (NON-NEURONOPATHIC) TYPE OCCURS WITH A FREQUENCY OF
1/50000. IT IS MOST COMMON AMONG ASHKENAZI JEWS. THE SYMPTOMS BEGIN IN
CHILDHOOD OR ADULTHOOD AND INCLUDE AN ENLARGED LIVER AND A GREATLY
ENLARGED SPLEEN (WHICH CAN LEAD TO ITS RUPTURE AND ADDITIONAL DAMAGE).
BONE WEAKNESS AND SEVERE BONE DISEASES ARE POSSIBLE. ALTERED SPLEEN AND
BONE MARROW CAUSE ANEMIA, THROMBOCYTOPENIA AND LEUKOPENIA.
ALTHOUGH THE BRAIN IS NOT DAMAGED IN THIS TYPE, THERE MAY BE
DISTURBANCES IN THE LUNGS AND KIDNEYS. PATIENTS SUFFER FROM FREQUENT
HEMATOMAS CAUSED BY THROMBOCYTOPENIA, AND FROM CONSTANT FATIGUE
(DUE TO A REDUCED NUMBER OF RED BLOOD CELLS). PATIENTS MAY LIVE TO
ADULTHOOD AND WITH A MODERATE FORM OF SYMPTOMS MAY BE ABSENT.
 TYPE II

• TYPE II IS A NEUROPATHIC INFANTILE FORM. THE AVERAGE AGE OF THE DISEASE

IS 3-5 MONTHS. NEUROLOGICAL COMPLICATIONS (SEVERE CONVULSIVE
SEIZURES, HYPERTENSION, APNEA, SEVERE MENTAL RETARDATION) MANIFEST
THEMSELVES BY 6 MONTHS. SYMPTOMS INCLUDE HEPATOSPLENOMEGALY,
WIDESPREAD PROGRESSIVE BRAIN DAMAGE, IMPAIRED EYE MOTILITY,
SPASTICITY, CONVULSIONS, LIMB RIGIDITY. SICK CHILDREN SUCK AND SWALLOW
POORLY; THEY USUALLY DIE AT THE AGE OF ONE TO TWO YEARS. THE
FREQUENCY OF OCCURRENCE IS 1/100000, HAS NO ETHNIC PREDISPOSITION.
 TYPE III
• TYPE III (SUBACUTE NEUROPATHIC (JUVENILE) FORM)TYPE 3 CAN BEGIN BOTH
IN CHILDHOOD AND IN ADULTS WITH A FREQUENCY OF 1/100000. IN MOST
CASES, IT IS CHARACTERIZED BY SLOW PROGRESSION AND MODERATION OF
NEUROLOGICAL SYMPTOMS. THE FIRST NEUROLOGICAL SIGN IS, AS A RULE,
OCULOMOTOR APRAXIA, A DISORDER OF OCULOMOTOR FUNCTIONS. AS THE
DISEASE PROGRESSES, ATAXIA, MUSCLE SPASTICITY AND DEMENTIA JOIN.
ALONG WITH HEPATOSPLENOMEGALY, OTHER ORGANS AND SYSTEMS ARE
INVOLVED IN THE PATHOLOGICAL PROCESS. SPLENOMEGALY IS PAINLESS AND IS
USUALLY DETECTED BY ACCIDENT. PATIENTS LIVE TO ADOLESCENCE AND
ADULTHOOD.
 PATHOLOGY

• ONE OF THE MAIN CAUSES OF DISABILITY IN TYPE 1 AND 3 OF GAUCHER'S

DISEASE IS BONE DAMAGE. VIOLATION OF NORMAL PHYSIOLOGICAL PROCESSES
OCCURS DUE TO THE ACCUMULATION OF LIPIDS IN OSTEOCLASTS AND THE
REPLACEMENT OF GAUCHER CELLS WITH INFILTRATES OF NORMAL ELEMENTS
OF THE BONE MARROW. DESPITE THE ENLARGEMENT OF THE LIVER AND ITS
DYSFUNCTION, CASES OF SEVERE LIVER FAILURE ARE RARE. RELATIVE PORTAL
HYPERTENSION IS MORE COMMON AS A CONSEQUENCE OF FIBROSIS.
 MUCOPOLYSACCHARIDOSIS TYPE I (MPS-I)
• MPS-I IS A GROUP OF METABOLIC DISEASES OF CONNECTIVE TISSUE
ASSOCIATED WITH IMPAIRED METABOLISM OF ACID GLYCOSAMINOGLYCANS
(ENGLISH GAG OR MUCOPOLYSACCHARIDES) CAUSED BY INSUFFICIENCY OF THE
LYSOSOMAL ENZYME OF GLYCOSAMINOGLYCAN METABOLISM ALPHA-L-
IDURONIDASE. THIS GROUP OF MUCOPOLYSACCHARIDOSES IS ASSOCIATED
WITH A HEREDITARY ANOMALY CAUSED BY A GENETICALLY DETERMINED
DEFECT OF A GENE LOCATED AT CHROMOSOME 4, WHICH IS INHERITED BY AN
AUTOSOMAL RECESSIVE TYPE. IT MANIFESTS ITSELF IN THE FORM OF
LYSOSOMAL ACCUMULATION DISEASE, WHICH LEADS TO VARIOUS DEFECTS OF
THE NERVOUS, BONE, CARTILAGE AND CONNECTIVE TISSUES.
ALL TYPES OF MPS ARE CHARACTERIZED BY COMMON
CLINICAL MANIFESTATIONS DUE TO THE
ACCUMULATION OF GAG IN VARIOUS TISSUES:
• 1. MULTI-SYSTEM NATURE OF THE LESION;
• 2. SPECIFIC FEATURES OF THE PHENOTYPE: CHARACTERISTIC CHANGES IN FACIAL FEATURES BY
THE TYPE OF GARGOILISM (ROUGH FACIAL FEATURES);
• 3. SKELETAL DEFORMITIES OF THE TYPE OF MULTIPLE DYSOSTOSIS(STIFFNESS OF SMALL AND
LARGE JOINTS);
• 4. HEPATOSPLENOMEGALY;
• 5. SENSORINEURAL HEARING LOSS;
• 6. CARDIOVASCULAR DISORDERS;
 CLINICAL MANIFESTATIONS (CONT.)

• 7. VARIOUS NEUROLOGICAL DISORDERS (DECREASED INTELLIGENCE, DELAYEDSPEECH

DEVELOPMENT, CHANGES IN MUSCLE TONE, TENDONSREFLEXES, ETC.);
• 8. CHANGES IN THE SKIN AND APPENDAGES (DRYNESS, COMPACTION OF THE SKIN WITHA
DECREASE IN THEIR ELASTICITY, HYPERPIGMENTATION IN THEDISTAL PARTS OF THE HANDS,
SCLERODERM-LIKE CHANGES, HYPERTRICHOSIS,FOCAL ALOPECIA, DEPIGMENTED AREAS OF
HAIR, STIFF HAIR);
• 9. FREQUENT INFECTIOUS DISEASES OF VDP, OBSTRUCTIVE SYNDROME,SLEEP APNEA;
• 10. PROGRESSIVE COGNITIVE IMPAIRMENT.
 MUCOPOLYSACCHARIDOSIS, TYPE 2 (HUNTER'S
DISEASE, HUNTER SYNDROME)

• MPS II A RARE RECESSIVE X‑LINKED GENETIC DISEASE FROM THE GROUP OF

LYSOSOMAL ACCUMULATION DISEASES. IT OCCURS AS A RESULT OF A
DEFICIENCY OF A NUMBER OF ENZYMES, WHICH LEADS TO THE ACCUMULATION
OF PROTEIN‑CARBOHYDRATE COMPLEXES AND FATS IN CELLS. THE SYNDROME
IS NAMED AFTER THE PHYSICIAN CHARLES A. HUNTER (1873-1955), WHO FIRST
DESCRIBED IT IN 1917.
 DIAGNOSTICS

• CLINICAL POLYMORPHISM IS CHARACTERISTIC OF MANY HMD , INCLUDING MPS. THIS

COMPLICATES THE DIFFERENTIAL DIAGNOSIS OF THESE DISEASES AT THE CLINICAL LEVEL, AND
ACCURATE DIAGNOSIS REQUIRES LABORATORY RESEARCH METHODS BASED ON THE USE OF
BIOCHEMICAL TESTS – THE EXAMINATION OF THE SPECTRUM AND AMOUNT OF EXCRETED
GAGS, THE DETERMINATION OF THE ACTIVITY OF LYSOSOMAL ENZYMES AND DNA
DIAGNOSTICS.
THANKS FOR
ATTENTION!!!