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Single gene disorder with Mendelian inheritance


Single gene disorders (Mendelian disorders) typically follow one of the three patterns of inheritance -

  1. Autosomal dominance
  2. Autosomal recessive
  3. X-linked

Autosomal dominant disorders

  • Normally a gene pair has two alleles.
  • When one allele becomes abnormal due to mutation it is called heterozygous state.
  • When both the alleles become abnormal due to mutation it is called homozygous state.
  • Autosomal dominant disorders are manifested in heterozygous state, i.e. only if one allele is abnormal the disease will be manifest

Autosomal dominant disorders







  • Huntington disease
  • Neurofibromatosis
  • Myotonic dystrophy
  • Tuberous sclerosis
  • Retinoblastoma
  • Polycystic kidney
  • Familial polyposis coli
  • Hereditary spherocytosis
  • Von- Willebrand dis


  • Marfan syndrome
  • EDS (some variant)
  • Osteogenesis imperfecta
  • Achondroplasia
  • Familial hypercholesterolemia
  • Acute intermittent porphyria

Note - Ehlers - Danlos syndrome (EDS) has all three Mendelian pattern of inheritance


Marfan syndrome

  • Marfan syndrome results from inherited defect in an extracellular glycoprotein fibrillin - 1 on chromosome - 15.
  • It has autosomal dominant inheritance.
  • Pathogenesis
    • Defect in fibrillin affects the elastic recoil of extracellular connective tissue.
    • Elastic fibres consist of a central core made up of elastin, surrounded by a peripheral network of micro fibrils that consists largely fibrillin.
    • Defect in fibrillin causes defective function of elastic fibres.
    • Microfibrils (containing fibrillin) are mainly distributed to Aorta, ligaments of joint and ciliary zonules of lens So, in Marfan syndrome these tissues are primarily affected.

In Marfan syndrome, aortic aneurism typically begins at the base of aorta and involves ascending aorta.

Clinical manifestations of Marfan syndrome

Skeletal abnormalities

  • Patient is unusually tall
  • Fingers and hands are long and slender and have spider like appearance (arachnodactyly).
  • Because the lower segment of the body largely contributes the tall stature, the
  • Severe chest deformities, pectus excavatum, pectus carinatum.
  • Scoliosis accompanied by kyphosis
  • High arched palate and high pedal arches or pes planus
  • Joint ligaments in hands and feet are lax.

Cardiovascular changes

  • Mitral valve prolapse can give rise to mitral regurgitation
  • Dilatation of ascending aorta owing to cystic medial necrosis (loss of medial support results in progressive dilatation of aortic valve ring and the root of the aorta giving rise to severe aortic incompetence)

Ocular changes

  • Bilateral subluxation or dislocation of the lens referred to as ectopia lens (typically in superio-temporal direction.)
  • Ocular globe is frequently elongated.

Associated changes

  • Spontaneous pneumothorax
  • Inguinal and incisional hernias.

Note - Some patients may develop hypermobility of joints like Ehlers - Danlos syndrome.


Ehlers Danlos syndrome (EDS)

  • EDS comprises a clinically and genetically heterogenous group of disorders that result from some defect in the synthesis or structure of collagen and characterized by hyperelasticity of skin and hypermobile joints.
  • Several types of EDS have been described based on the extent to which the skin, joints and other tissues are involved, mode of inheritance and biochemical analysis.
    • Type I – Severe
    • Type II – mild ---} Classic EDS Involvement of both joints & skin.
    •  Type III - Hypermobile EDS Joints > skin
    • Type IV - Vascular EDS Vascular and intestinal involvement.
    • Type V Similar to classic
    • Type VI - Ocular scoliotic EDS Eye and spine involvement.
    • Type VII - Dermatosparactic EDS Dysmorphic features
    • Type VIII Parodontal EDS Dental involvement.
  • EDS shows all patterns of mendelian inheritance -
    • Type I, II, III, IV, VII A & B, VIII Autosomal dominant.
    • Type IV & VII C Autosomal recessive
    • Type V X-linked recessive.
  • Clinical manifestations
  1. Skin
  • Skin is hyperextensible
  • Patient can develop cigarette - paper scar.
  • There is easily bruisability.
  1. Joints
    There is ligament laxity and hypermobility of joint Patient can bend thumb back to touch forearm. Dislocation of hip or other joints may occur.
  2. Others
  • Mitral valve prolapse     }

                                                } In classic (type I) EDS

  • Diaphragmatic hernia   }
  • Rupture of colon and large arteries In vascular (type IV) EDS.
  • Rupture of cornea and retinal detachment}
  • Kyphoscoliosis
  • Blue sclera    }      In ocular – Scoliotic (type VI) EDS.
  • Absorptive
  • Absorptive periodontosis with premature loss of teeth in periodontic (type VIII) EDS.

Autosomal recessive disorders

Autosomal recessive disorders are manifested in homozygous state, i.e. when both alleles at a given gene locus are mutant.






  • Cystic fibrosis
  • Phenylketonuria
  • Galactosemia
  • Homocystinuria
  • Lysosomal storage dis
  • 1-antitrypsin deficiency
  • Wilson disease
  • Hemochromatosis
  • Glycogen storage disorders
  • Sickle cell anemia
  • Thalassemias
  • Congenital adrenal hyperplasia
  • Albinism


  • EDS (some variants)
  • Alkaptonuria


  • Friedreich ataxia
  • Spinal muscular atrophy
  • Neurogenic muscular atrophies


Important lysosomal storage diseases


Deficient enzyme

Accumulating metabolites


  • GM1, gangliosidosis
  • GM2 gangliosidosis

(i) Tay-sachs disease

(ii) Sand off disease


  • -galactosidase


Hexosaminidase - subunit

Hexosaminidase - subunit


GM1 ganglioside


GM2 ganglioside

GM2 ganglioside

Glycogenosis Type II

  • Pompe disease
  • -1, 4, glucosidase



  • MPS I H (Hurler)
  • MPS II (Hunter)


  • -L-Iduronidase

Iduronate sulfatase


Dermatan sulfate

Heparan sulfate


  • Metachromatic leukodystrophy
  • Krabbe disease
  • Gaucher disease
  • Fabry's disease
  • Niemann-Pick disease


Arylsulfatase A



  • -Galactosidase A






Cerarnide trihexoside



  • Wolman disease

Acid lipase


Cholesterol ester triglyceride


Niemann's picks disease

  • The clinical features of Niemann Picks disease.
  • Presence of hepatosplenomegaly
  • Mental retardation
  • Delayed growth

The pathological feature of Niemann's Picks disease is characterized by

  • The presence of large foam cells in bone marrow, liver and spleen.
  • Electron microscopy will show pleomorphic inclusion, of lipids in Lysosomes. These lipids are enclosed in concentric or parallel lamellae.
  • All the above mentioned features can be seen in Gaucher's disease too but the electron microscopy in Gaucher's is characterized by the presence of elongated distended lysosomes containing the stored lipids in stacks of bilayers.

X-linked disorders

  • Except for a few conditions, all X-linked disorders are X-linked recessive.
  • As male has only one X-chromosome, the male with affected gene on X-chromosome will always manifest the disease.
  • On the other hand, female has 2 X chromosomes, heterozygous female will be carrier because of expression of normal allele on the other X-chromosome.
  • Note Female with Turner syndrome (only one 'X' chromosome) can manifest X-linked recessive disorders.
  • 50% boys of the carrier mother will be affected.
  • All daughters of affected father will become carrier, i.e. affected father will transmit the defective X chromosome to all the daughters. .
  • Father will not transmitt the disease to son as boys do not inherit X-chromosome from father.

X-linked Recessive disorders






  • Duchene muscular dystrophy
  • Chronic granulomatous disease
  • Hemophilia A & B
  • G-6-PD deficiency
  • Agammaglobulinemia
  • Wiskott-Aldrich syndrome
  • Diabetes insipidus
  • Lesch Nyhan syndrome
  • Fragile-X-syndrome
  • Color blindness


X-linked dominant disorders

  • Vitamin D resistant rickets
  • Familial hypophosphatemia


X-linked dominant inheritance

  • Even a single abnormal X chromosome is sufficient to express the disease.
  • All of the female off springs of a diseased male XY will receive the abnormal X chromosome and express the disease, where as none of the male offspring to the diseased father will have the disease. (as sons don't receive their X chromosome from father.
  • A diseased mother can transmit the abnormal X chromosome to both daughter and sons equally.

Important facts

  • If female is transmitting the disease to all off springs (both males and females) and male is not transmitting the disease to any child, it is mitochondrial inheritance.
  • If male is transmitting the disease only to daughters (all daughters) and not to the sons whereas female transmit the disease to half daughters and half of sons, it is X-linked dominant.
  • If only males are affected in a pedigree, it is likely to be X-linked recessive disease (females act as carriers; only transmit the disease and themselves remain unaffected).
  • If there is no sex-predilection and affected individuals transmit the disease to half of the off springs, it is autosomal dominant disorder.
  • If there is no sex-predilection and affected individuals transmit the disease to one fourth of the off springs, it is likely to be autosomal recessive disorder.

Disorders with multifactorial inheritance

  • The multifactorial disorders result from the combined actions of environmental influences and two or more mutant genes having additive effects.
  • Multifactorial disorders are-
  1. Cleft lip/cleft palate              
  2. Congenital heart diseases
  3. Coronary heart disease                          
  4. Hypertension
  5. Diabetes mellitus          
  6. Gout                   
  7. yloric stenosis

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