GENETIC DISORDERS MBBS NOTE

The group of disorders affecting the foetus during intrauterine life (genetic as well as developmental) and paediatric age group.
Groups of genetic diseases include :

Developmental defects
Cytogenetic (Karyotypic) defects
Single-gene defects (Mendelian disorders)
Multifactorial inheritance disorders
Storage diseases (Inborn errors of metabolism)

Congenital Disorders

Non Genetic:
Developmental defects – Malformations
Genetic Disorders
Chromosomal
Gene - Mendelian
Multifactorial

Human germ cells (ova and sperms) contain 23 chromosomesm(haploid or 1N)
while all the nucleated somatic cells of the human body contain 23 pairs of chromosomes (diploid or 2N)— 44 autosomes and 2 sex chromosomes, being XX in females (46, XX) and XY in males (46, XY).

Human germ cells (ova and sperms) contain 23 chromosomesm(haploid or 1N)
while all the nucleated somatic cells of the human body contain 23 pairs of chromosomes (diploid or 2N)— 44 autosomes and 2 sex chromosomes, being XX in females (46, XX) and XY in males (46, XY).

Chromosomal banding techniques are employed for study of classes of chromosomes.
Chromosomal bands are unique alternate dark and light staining patterns.
Banding techniques include:

i) G-banding (Giemsa stain);
ii) Q-banding (quinacrine fluorescence stain);

iii) R-banding (reverse Giemsa staining); and

iv) C-banding (constitutive heterochromatin demonstration).

Cytogenetic disorders- structural (nondisjunction during gametogenesis, numerical-(from error during division)
Monosomy – associated with one less normal chromosome( 2n-1)
Trisomy- one extra chromosome( 2n+1)
Mosaicism( Mitotic errors in zygote)- associated with 1 or more population of cells, some normal chr., others with extra or missing chr.
Mendelian (single gene mutation)

Mutations

Genome: whole set – Polyploidy 4n, 8n etc.
Chromosomal: change in chromosome.
Number: Trisomy, monosomy
Structure: Deletion, Translocation etc.
Gene: Submicroscopic.
Point mutation – single base sequence
Deletions -
Insertions

Cytogenetic Abnormalities:

Abnormal number of chromosomes:
Non-disjunction - Down’s Syndrome
Anaphase lag - Turner’s xxx
Abnormal Structure: (normal no)
Deletion of short arm 5q- Cri-du-chat syndrome
Inversion -
Translocation - Ph Chromosome - t(9:22) CML

TURNER SYNDROME

Hypogonadism in Phenotypic females
Complete or partial Monosomy of X Chr.
45,X most common
Mosaics also occur (eg., 45,X/46,XX)

Structural abnormalities of X chromosomes

Deletion of the small arm, resulting in the formation of an isochromosome of the long arm
Deletion of the proportions of both long & short arms resulting in the formation of a ring chromosome
Deletion of portions of the short or long arm

KLINEFELTER SYNDROME

Male hypogonadism
2 or more X chromosomes and at least one(1) Y chromosome.
47,XXY most common(80%)
Mosaics also-(e.g., 46,XY/47,XXY)

CLINICAL FEATURES

Commonest cause of male infertility
Body Habitus- Eunuchoid
Failure of Male secondary sexual character
Gynecomastia
Female distribution of hair
Atrophic testis with hyperplasia of leydig cells
FSH & Estrogen levels elevated, testosterone levels low
Minimal or no Mental retardation

DOWNS SYNDROME (Trisomy 21)

Most common 1 in 800 births
Complete extra chromosome 21(47,XY,+21)
Increased maternal age -1 in 25 above 45 years of age
Cause is meiotic non disjunction of chromosome 21 in the ovum
Mosaic variant 1%

Clinical features

At birth evident
Flat facial profile
Oblique palpebral fissures
Epicanthic folds- “Mongolism”
Mental retardation- 80%
Shy & Gentle!
Mosaics- Near normal intelligence

40% congenital heart disease- ASD, VSD, AV valve malformations
Atresias of esophagus, small bowel
10 to 20 fold increased risk of- Acute leukemias (AML, ALL)
All above 40y develop Alzheimer disease
Abnormal immune response- Predisposed to serious infections in lungs, thyroid autoimmunity

SINGLE-GENE DEFECTS (MENDELIAN DISORDERS)

The classic laws of inheritance of characteristics or traits were outlined by Gregor Mendel in 1866.
Single-gene defects follow the classic mendelian patterns of inheritance and are also called mendelian disorders.
These disorders are the result of mutation of a single gene of large effect.

ENZYME PROTEIN DISORDERS OR LYSOSOMAL DISORDERS

Mutation of gene

Alters the protein synthesis

Metabolic block

NORMAL METABOLISM

Enzyme act as catalyst

In case of deficiency

accumulation of intermediates

decrease in end product

no inactivation of tissue damaging sub

PHYSIOLOGY OF LYSOSOMES (HYDROLYTIC ENZYMES)

Synthesized in ER
Compelled in Golgi
complex with M 6 P
binds to receptors
separated as vesicles
Fused with lysosomes
Digests the macromacules
metabolic intermediates
intracellular organelle
phagocytosed material

PATHOLOGY OF STORAGE DISORDERS

Abnormal enzymes
No proper digestion (phagocytosis, organs, metabolism)
Increase accumulation in the lysosomes
Interfere in normal cell function
C/F depends on site of enzymes
glycosidase ---- neuron
muco polysaccharide-----every organ
Rich in Mononuclear Phagocytic cells (MPC) which degrades many substance
MP Cells are rich in liver, spleen, LN, Marrow etc.

CLASSIFICATION OF L.S. D

GLYCOGEN STORAGE DISORDERS
Von gierkes
Pompe
SPHINGOLIPIDOSES(GANGLIOSIDOSIS)
GM1 gangliosidosis( inf, juv)
GM2 (Tay sachs, Sandhoffs)
SULPHATIDOSES
Gouchers
Niemen picks
MUCOPOLYSACHARIDOSIS
6 types
MUCOLIPIDOSES
OTHER

VON GIERKES DISEASE

Glycogen start accumulating
No glucose release
Hypoglycemia
Increase fat metabolism
Deficiency of Glucose 6 Phosphatase
Increase lactate, pyruvate & ketosis
C/F Childhood
hepatomegaly
failure to thrive
skin xanthoma
cytoplasm clear glycogen

POMPES DISEASE

Decrease in acid maltase
Glycogen accumulation in heart and muscle
C/F cardiomegaly, cardiorespiratory failure
Hypotonia and muscle weakness
Die within 2 years
In adult form mainly skeletal muscle involved

TAY SACHS DISEASE

Common type o f GM2.
Mutation of Ch 15. hexosaminidase deficiency
Gangliosides accumulates in
liver, spleen, heart , CNS, Retina.
Ballooning of neurons
cytoplasm filled with gangliosides
cytoplasmic vacuoles
special stain oil red O, Sudan black
EM vacuoles showing onion skin appearance

TAY SACHS DISEASE

Progressive destruction of neurons
Proliferation of microglia.
Involve cerebellum, basal ganglia, ANS, cord.
Involve the MPC.
Retina shows cherry red spot

C/F OF TAY SACH

Varies depending on the degree of deficiency
Normal at birth
By 6 month motor and mental deterioration
muscle flaccid
motor in coordination
Mental
dementia,
blindness
pathetic
cherry red spot.

TAY SACHS DISEASE

Diagnosis

enzyme assay
DNA analysis

NIEMANN -PICK DISEASE

Accumulation of sphingomyelin & cholesterol
Deficiency of sphingomyelinase
Sphingomyelin present in cell and organeller membrane
No degradation of membrane

NIEMANN -PICK DISEASE

TYPE A

severe and infantile form
extensive neuronal involvement
viscera also accumulated with SM
progressive disease
death with in 3 yrs.

NIEMANN -PICK DISEASE

TYPE B

CNS not involved
adult form
organomegaly

MORPHOLOGICAL CHANGES

TYPE A
Absence of sphingomyelinase
accumulation of sphingomyelin in MPC
Cells are enlarged, distended lysosomes
filled with sphingomyelin and cholesterol
small uniform, multiple vacuoles & foamy cytoplasm
frozen section & special stain for fat.
EM Shows zebra bodies

MORPHOLOGICAL CHANGES

TYPE A

lipid laden cells in spleen, LN, marrow, GIT, lung.
splenomegaly up to 10 times,
moderate hepatomegaly, LN enlargement.
Brain sulci widen, shrunken gyri.
all part of nervous system are involved.
Neurons are ballooned, and decreased in number.
Cherry red spot in the retina.

CLINICAL FEATURES OF NIEMANN- PICK

Start at birth
Evident by 6 months
Hepato splenomegaly and failure to thrive
Lymphadenopathy
Fever
Vomiting
Death within 2 years

DIAGNOSIS OF NIEMANN- PICK

Sphingomyelinase assay in liver & marrow.
DNA probe analysis

GAUCHERS DISEASE

Glucocerebrosidase deficiency
Glucocerebroside accumulation in lysosomes
Present in phagocytic cells and CNS
It is the most common disease
Cluster of Autosomal recessive disease
There are 3 types

TYPE 1 GAUCHERS (CLASSIC/ADULT FORM)

80% of Gauchers
Glucocerebrosides accumulates in the MPC
Spleen, liver, bone marrow, lymph nodes and skeletal muscles are involved
Brain is not involved.
Life is short but not marked

TYPE 2 GAUCHERS (INFANTILE FORM)

Neuropathic form
Progressive involvement
No detectable glucocerebrosidase
Hepato splenomegaly
Patient die in early age

TYPE 3 GAUCHERS (JUVENILE FORM)

It is between 1 and 2
Progressive involvement of CNS

MORPHOLOGY OF GAUCHERS

Massive accumulation in the MPC all over
Gauchers cells liver, spleen, marrow, LN
Fibrillar type of cytoplasm
Crumpled tissue paper appearance.
Cells up to 100u
Eccentric nucleus
PAS positive
EM Elongated lysosomes with lipids
Spleen enlarged to 10 times
Pale and matted surface (focal accumulation)
Moderate lymphadenopathy

MORPHOLOGY OF GAUCHERS

BONE
Erosion
skeletal deformity
soft and gray
pathological fracture
CEREBRUM
Gauchers cells in the virchow robins space
No lipids in the neurons
Neurons are destroyed possible toxic effects of surrounding cells

CLINICAL FEATURES Type 1 Gauchers

Adult type
Pancytopenia due to hypersplenism
Pathological fracture
Bone pain
Compatible with long life

TYPE 2 AND 3 OF GAUCHERS

Convulsion
Mental deterioration
Liver, spleen and LN are affected

MUCOPOLYSACHARIDOSIS

Is a group of disorders
Enzymes degrading mucopolysacharides
MP are glycosamino glycans or lecithin complex COH linked to proteins.
Accumulation of dermatan, keratan, heparan and chondroitin sulphate.
The enzymes cleaves terminal sugar and allow to digest further.

MUCOPOLYSACHARIDOSIS cont….

Abnormalities in enzymes in the lysosomes
Accumulation of substance in the lysosomes
Cause somatic and neurological problems
There are 7 types
Hunter is X linked and all other are Autosomal
Progressive disorders of multiple organs involves liver, spleen, heart and vessels.

MORPHOLOGY OF MUCOPOLYSACHARIDOSIS

Substance accumulates in the MPC, endothelium and SMC.
It involves the spleen, liver . LN, heart and vessels.

MICROSCOPY OF MUCOPOLYSACHARIDOSIS

The cells are ballooned with mucopolysacharides.
Cytoplasm have many clear vacuoles
EM shows swollen lysosomes filled with granular PAS positive materials.
Presence of zebra bodies in lysosomes

CLINICAL FEATURES

Hepato splenomegaly and skeletal deformities.
Sub endothelial deposition cause myocardial ischemia and MI.
HURLERS
Alpha 1 iduronidase deficiency
Hepato splenomegaly
growth retardation
death in 6 to 10 years due to CVS complication
HUNTERS
It is very mild disease
corneal clouding

TUMORS OF INFANCY AND CHILDHOOD

Tumors and Tumor-like Conditions
MC neoplasms of childhood = soft-tissue tumors (mesenchymal) - adults
Benign tumors more common than cancers
2% of all malignant tumors occur in infancy and childhood
Tumor-like conditions

Heterotopia (or Choristoma )

– Normal cells or tissues that are present in abnormal locations

– pancreatic tissue in stomach or small intestinal wall

– adrenal cells found in the kidney

Hamartoma

– Excessive, focal overgrowth of cells / tissues native to the organ but not having normal architecture

– Examples = Adenomas of the liver, Hemangiomas, lymphangiomas, rhabdomyomas

Benign Tumors

Hemangioma = MC tumors of infancy

– Cavernous and capillary types

– Common on face and scalp

– Flat , larger lesions = port-wine stains

– Hereditary disorder:- von Hippel – Lindau (VHL) disease.

Lymphatic tumors

Lymphangiomas (hamartomatous or neoplastic)

– increase in size after birth

Encroach on vital structures in mediastinum or nerve trunks of axilla
Lymphangiectasis = not progressive,

Fibrous tumors

More common =Fibromatosis, sparsely cellular (multiple fibromas)
Congenital - infantile Fibrosarcomas {t (12:15)}

– ETV6-NTRK3 fusion transcript = diagnostic marker

– ETV6 (transcription factor) and NTRK3 gene is tyrosine kinase.

Teratomas

Histological maturity correlates with biologic behavior
well-differentiated cystic lesions (mature teratomas),
Age = two peaks ( 2 years of age & late adolescence or early adulthood)
Sacrococcygeal teratomas = MC ( more common in girls (M:F::4:1)
75% are mature and benign teratomas
Other sites of teratomas =testis, ovaries, midline

Malignant Tumors

– Incidence and types

– Neuroblastic tumors

– Wilm’s tumor

Neuroblastic tumors-
Tumors of the sympathetic ganglia and adrenal medulla
Derived from neural crest cells
Neuroblastoma

– MC extra cranial solid tumor of childhood

– median age at diagnosis = 18 months

– MC diagnosed tumor of infancy

– Most of them are sporadic

Most characteristic features

– spontaneous or therapy-induced differentiation of primitive neuroblasts into mature elements

– spontaneous tumor regression

– wide range of clinical behavior and prognosis,

Children younger than 18 months of age have better prognosis
5-year survival is generally 40%

Malignant = Neuroblastic tumors contd..

Morphology
Site = 40%arise in the adrenal medulla (MC site) followed by paravertebral region of abdomen (25%), posterior mediastinum (15%) and other sites (pelvis, Neck, brain (cerebral neuroblastomas)
Size = minute nodules (in situ lesions) to 1 kg in weight

– Larger tumors have necrosis, cystic softening, and hemorrhage

– In situ ones are more frequent and spontaneously regress

Histologically
LM= Made of small, primitive cells with dark nuclei, scant cytoplasm, and poorly defined cell borders ; Karyorrhexis and pleomorphism are prominent; rosettes (Homer-Wright pseudorosettes)

IHC =positive immuno –markers ( neuron-specific enolase (NSE), Synaptophysin, Chromogranin A, S100 protein etc.,)
EM =cytoplasmic catecholamine-containing secretory granules with peripheral halo (dense core granules)

– Some show signs of maturation into ganglioneuroblastoma and ganglioneuroma

– Maturation is spontaneous or therapy-induced

– Differentiated lesions are accompanied by Schwann cells.

Metastases to lymph node or/and liver, lungs, bone marrow, and bones

Malignant = Neuroblastic tumors contd..

Staging.
Stage 1: Localized with complete gross excision
Stage 2: Localized with incomplete gross resection
Stage 3: Unresectable unilateral, across the midline
Stage 4: distant metastasis
Stage 4S ("S" = special): infants younger than 1 year & dissemination limited to skin, liver, and/or bone marrow
Clinical Course and Prognostic Features

- Under age 2 years= present with large abdominal masses, fever, weight loss

- Older children = insignificant until metastases; present proptosis (common metastatic site) and ecchymoses

– multiple cutaneous metastases ="blueberry muffin baby"

– 90% of neuroblastomas =produce catecholamines, helps in diagnosis (hypertension is less frequent ) vanillylmandelic acid [VMA] and homovanillic acid [HVA]) in urine or blood

Prognosis
"core" criteria used for risk stratification and therapeutic decision =age, stage, NMYC status, histology, and DNA ploidy

Wilm’s tumor

MC primary renal tumor of childhood
Peak age =between 2 and 5 years
Improvements in the cure rates
Pathogenesis and Genetics
Increased association with four syndromes

– 1. WAGR syndrome =aniridia, genital anomalies, mental retardation; deletions of 11p13 (WT1 gene)

– 2. Denys-Drash syndrome= higher risk for Wilm's tumor (∼90%); gonadal

dysgenesis (male pseudohermaphroditism) and early-onset nephropathy; dominant-negative missense mutation in the zinc-finger region of the WT1 gene and increased risk for gonadoblastomas (WT1=critical for normal renal and gonadal development)

– 3. Beckwith-Wiedemann syndrome (BWS) ="WT2”gene

Genomic imprinting ; overexpression of IGF-2 (embryonal growth factor) is critical ; Organomegaly, macroglossia, hemi-hypertrophy, omphalocele, adrenal cytomegaly;

– 4. β-catenin associated Wilms tumors ; belong to WNT (wingless) signaling pathway; 10% of sporadic cases, gain-of-function mutations

Nephrogenic rests =precursor lesions of Wilms tumors

Clinical Features =large abdominal mass with hematuria, abdominal pain, intestinal obstruction and HTN
Pulmonary metastases
Prognosis depends on (poor prognostic features)

– Anaplasia,

– loss of genetic material on chromosomes 11q and 16q,

– gain of chromosome 1q

Risk of Second malignancies

– soft-tissue sarcomas,

– leukemia and lymphomas,

– breast cancers

1 stromal -Usually fibrotic or myxoid in nature with Paler type of cells

2 blastemal - Bunch of less undifferentiated

Dark cells Less differentiated therefore worse prognosis

3Epithelial -Form of abortive tubules or glomeruli as epithelial rosettes

Better differentiated, therefore better prognosis.

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GENETIC DISORDERS MBBS NOTE

GENETIC DISORDERS MBBS NOTE

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