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Autosomal dominant pedigree: 

Autosomal dominant pedigree 7 8 9 4 3 6 5 1 2 I II III

Autosomal dominant inheritance: 

Autosomal dominant inheritance Phenotype appears in every generation Except if new mutation ascertainment error or oversight Each child of an affected parent has a 50 % chance of inheriting the trait Male-to-male transmission essentially confirms the mode of transmission Males and females equally likely to be affected

Autosomal dominant inheritance: Subtle points: 

Autosomal dominant inheritance: Subtle points The phenotype appears in every generation, and each affected individual has an affected parent, i.e. a vertical pattern of transmission. Exceptions to this rule occur if there is a new mutation, or there is reduced penetrance of the phenotype. Individuals can also be mislabeled, since mild signs can be overlooked. Phenotypically normal parents do not transmit the trait, unless there is lack of penetrance, or the apparently 'normal' parent has unrecognized signs. Male to male transmission occurs, and is effectively diagnostic of autosomal dominant transmission (the existence of true Y linked disorders with male fertility is not proven).

Autosomal dominant, one affected parent: 

Autosomal dominant, one affected parent 2 affected 2 unaffected

Most enzymatic pathway diseases are recessive: 

Most enzymatic pathway diseases are recessive

Of course, there are exceptions: Acute Intermittent Porphyria: 

Of course, there are exceptions: Acute Intermittent Porphyria Adult onset, often medication induced, intermittent neurologic symptoms: Motor neuropathy, may progress to quadriplegia and respiratory paralysis Acute abdominal pain, with ileus, mimicking surgical abdomen, constipation Seizures Psychiatric symptoms, including psychosis Medications which may induce attacks include: Barbiturates, anticonvulsants, sulfa drugs, alcohol, hormonal changes

Acute Intermittent Porphyria II: 

Acute Intermittent Porphyria II Urine has dark red color, especially if allowed to stand in light 1/40,000 prevalence, much higher in Northern Sweden, affects 1/900; women affected 50 % more often; King George III of England? Defect is in gene for porphobilinogen (PBG) deaminase (aka uroporphyrinogen synthase) PBG deaminase is a rate limiting enzyme in heme synthesis whose activity can be perturbed by other chemicals

Acute Intermittent porphyria III: 

Acute Intermittent porphyria III Gene lies at 11q23. At least 14 mutations known Best screening test is direct measurement of urinary and fecal porphyrins during acute attack. When asymptomatic, enzyme measurement is more sensitive. Differential diagnosis of porphyria: Variegate porphyria: Neurologic symptoms same as AIP, but also with bullous skin ulcerations in sun exposed areas. Common in both black and white South Africans (1/400). Defect in protoporphyrinogen oxidase Hereditary coproporphyria: Similar to variegate; defect in coproporphyrinogen oxidase.


Porphyria A treatable as well as preventable disease: Acute treatment: Avoid precipitating factors Hematin to repress ALA synthetase IV fluids and glucose



Autosomal dominant inheritance with new mutation: 

Autosomal dominant inheritance with new mutation 7 8 9 4 3 6 5 1 2 I II III

Hereditary diseases with treatable complications: 

Hereditary diseases with treatable complications

Autosomal dominant, both parents affected: 

Autosomal dominant, both parents affected 1 affected homozygote, may be most severely affected 2 affected heterozygotes 1 normal

Achondroplasia mutation: 

Achondroplasia mutation


Achondroplasia Most common form of short limbed dwarfism Features: Long, narrow trunk Short extremities, particularly proximally (rhizomelia), trident configuration of hands Large head with frontal bossing, hypoplasia of midface, narrow foramen magnum  obstructive hydrocephalus Exaggerated lumbar lordosis (forward curvature of spine) Normal intelligence (reduced mental capacity may indicate respiratory dysfunction during sleep) Early complications: Intracerebral hemorrhage, cervical dislocations more likely to occur during delivery Late complications: Obesity, otitis media, orthopedic, obesity, spinal nerve root and spinal cord compression (especially atlanto-axial dislocations)

Achondroplasia II: 

Achondroplasia II Genetics: 85 % are new mutations. Advanced paternal age a factor Completely penetrant; Prevalence 1/10,000 Mutation mapped to 4p16.3, near Huntington disease locus Vast majority of mutations cause G  A at base 1138 of mRNA (G  R at amino acid 380, G380R) for the fibroblast growth factor receptor 3. A391E mutation of FGFR3 results in Crouzon syndrome (craniosynostosis: premature closure of cranial sutures) with acanthosis nigricans Crouzon syndrome without acanthosis nigricans caused by mutations of the FGFR2 gene (locus heterogeneity) Mutations elsewhere in FGFR3 gene cause thanatophoric dysplasia (allelic heterogeneity)

Achondroplasia III: 

Achondroplasia III FGF receptors mediate a variety of cellular proliferative and differentiative processes Mutation occurs in transmembrane domain of this tyrosine kinase-type receptor Homozygous condition very severe to fatal Other mutations in FGFR3 receptor cause distinct clinical syndromes (allelic heterogeneity) Diagnosis: clinical phenotype, confirmed by PCR test of FGFR3 gene

Achondroplasia IV: 

Achondroplasia IV Management: Cesarean section if achondroplasia recognized prenatally Monitor closely for neurologic signs in newborn period, including MRI, polysomnography, evoked potentials, follow head circumference Follow for neurologic and orthopedic complications throughout life General medical care to minimize development of obesity

Autosomal dominant, both parents affected: 

Autosomal dominant, both parents affected 1 affected homozygote, may be most severely affected 2 affected heterozygotes 1 normal

Marfan syndrome: 

Marfan syndrome Skeletal: Tall stature Disproportionately long limbs and digits (arachnodactyly) Anterior chest deformity Joint laxity Scoliosis (convex to right in most) and thoracic lordosis High arched palate Ophthalmologic: Ectopia lentis (superior-temporal lens dislocations) Blue sclerae Cardiovascular: Dilation of aortic root  ascending aortic aneurysm,dissection, aortic regurgitation Mitral valve prolapse  mitral regurgitation

Arachnodactyly: figure from Marfan’s original paper: 

Arachnodactyly: figure from Marfan’s original paper

Marfan disease: 

Marfan disease

Dominant mutations: Pathophysiologic mechanisms: 

Dominant mutations: Pathophysiologic mechanisms Often affect proteins which interact with other proteins to form a protein complex Mutant protein may bind to its usual partner protein(s), but the resulting complex is inactive: a dominant negative mutation The mutation may give the new protein new functions or augment its usual function in a deleterious way: dominant gain-of-function mutation

Marfan syndrome II: 

Marfan syndrome II Pulmonary: Pulmonary blebs  spontaneous pneumothorax 15 - 25 % new mutations, increased paternal age may be factor Prevalence: 1/20,000 Mutations of fibrillin I gene on 15q21.1 23 known mutations, mostly missense. Most families have different mutations Fibrillin 350,000 Dalton protein Major component of extracellular microfibrils Mutations appear to act in dominant negative fashion: The abnormal protein (usually prematurely terminated) blocks the formation of normal microfibrils

Marfan syndrome III: 

Marfan syndrome III Diagnosis: Clinical signs Differential diagnosis: Homocystinuria: Similar physical appearance Mental retardation common Inferior-nasal subluxation of lens Arterial thromboses homocysteine in urine Positive family history Decreases fibrillin deposition by cultured skin fibroblasts ? Molecular diagnosis by polymerase chain reaction, or reverse transcriptase - PCR, in vitro translation assay.

Marfan syndrome IV: 

Marfan syndrome IV Management: Complications must be anticipated and prevented! -blockers Periodic cardiologic evaluations Great vessel repair/replacement when indicated Cardiac valvular replacement when indicated Rehabilitation medicine and orthopedic evaluations to minimize scoliosis

Myotonic dystrophy: 

Myotonic dystrophy

Myotonic muscular dystrophy (Steinert disease): 

Myotonic muscular dystrophy (Steinert disease) Clinical hallmarks: Facial weakness, distal extremity weakness, neck muscle weakness, myotonia (usually not prominent) frontal baldness, cataracts, gonadal atrophy, cardiomyopathy, diabetes, percussion myotonia on exam Congenital myotonic dystrophy, usually maternally transmitted, extremely severe myopathy and mental retardation present at birth. Prevalence: 5 - 10/100,000 Inheritance: Autosomal dominant, with maternal anticipation (more severe disease in subsequent generations)

Myotonic dystrophy: 

Myotonic dystrophy Chromosome: 19q13 Gene affected: Myotonin,encodes a 53 kD protein believed to be a protein kinase. Mutation: Expanded CTG trinucleotide repeat in 3’ UTR of myotonin gene, Normal range: 5-27 repeats; mildy affected: 50 - 80 repeats; severely affected:hundreds to thousands of repeats. Level of unaffected gene mRNA reduced as well as that of mutated gene: dominant negative effect at RNA level Genetic test: PCR test (beware false negatives!), Southern blot test (essential if PCR does not show two distinct products) Prenatal testing available

Anticipation in Myotonic dystrophy: 

Anticipation in Myotonic dystrophy

Age of onset: Huntington disease: 

Age of onset: Huntington disease

Movie break: 

Movie break

The man: 

The man

Huntington disease: 

Huntington disease Clinical features: Adult onset (mean 30-40 years) progressive choreoathetosis, dementia, psychiatric disturbances, dysphagia and dysarthria, impaired saccadic eye movements Inheritance: Autosomal dominant with paternal anticipation Chromosome: 4p16.3 Mutation: Expansion of CAG repeat in huntingtin gene, encodes a ubiquitously expressed protein of unknown function; Amino terminus with the expanded polyglutamine tract is liberated by caspases and then forms toxic protein aggregates Testing: Gene testing available

Huntington disease: Gross neuropathology: 

Huntington disease: Gross neuropathology HD brain Normal brain

A famous headline: 

A famous headline

Distribution of Huntingtin repeats: 

Distribution of Huntingtin repeats

Trinucleotide repeat expansions in a Venezuelan Huntington disease family: 

Trinucleotide repeat expansions in a Venezuelan Huntington disease family

Homozygous Huntington disease: 

Homozygous Huntington disease

Spinocerebellar ataxia I (SCA I): 

Clinical features: Adult (mean age 35) onset progressive ataxia, peripheral neuropathy, Babinski signs, bulbar palsies, probably accounts for 10-15 % of inherited ataxias Inheritance: Autosomal dominant, with paternal anticipation Chromosome: 6p23 Mutation: Expansion of CAG repeat region in ataxin gene, which encodes a protein of unknown function Testing: NCV, gene testing available Spinocerebellar ataxia I (SCA I)

Machado-Joseph Disease (SCA III): 

Clinical features: Adult (us. after 40) onset gait ataxia, Parkinsonian signs, ophthalmoparesis, fasciculations, leg areflexia, Babinski signs, nystagmus, mild cerebellar tremors, diabetes Inheritance: Autosomal dominant Accounted for about 40 % of dominant ataxias in one study Chromosome: 14q24.3-q32 Mutation: CAG repeat expansion in novel gene of unknown function Testing:Gene testing available Machado-Joseph Disease (SCA III)

More triplet repeat disorders: 

More triplet repeat disorders Spinocerebellar ataxias Type 2: Ataxin-2; 6p23 Type 6: Calcium channel 1A4 gene 19p13 allelic to familial hemiplegic migraine (missense mutations) and episodic ataxia-2 (premature terminations) Syndrome also can be caused by missense mutation Type 7: (syndrome includes retinal disease with blindness): ataxin-7; 3p21 Type 8: 13q21: CTG repeat disorder in non-translated region of gene (like myotonic dystrophy) -extreme expansions (>800) may not be pathogenic

Dentatorubropallidoluysian atrophy (DRPLA): 

Clinical features: Myoclonus epilepsy, dementia, ataxia, choreoathetosis,onset usually in the 20s and death in the 40s. Inheritance: Autosomal dominant Chromosome: 12pter-p12 Mutation: CAG repeat expansion in novel gene of unknown function (gene was discovered in explicit search for CAG repeat containing genes) Testing: Gene testing available Dentatorubropallidoluysian atrophy (DRPLA)

Some important features of triplet repeat disorders: 

Some important features of triplet repeat disorders All CAG repeat disorders are in the coding regions of the respective genes and are of about the same size (about an extra 20 repeats, usually) The non-CAG repeat disorders lie in non coding regions and repeat size increases can be very large (hundreds to thousands) Intermediate expansions may not cause disease, but may be much more likely to expand Anticipation can occur with either type Occurrence of anticipation may depend upon gender of transmitting parent

Neurofibromatosis I: 

Neurofibromatosis I One of the phakomatoses Highly variable expressivity even within same family Clinical features, two or more of: 6 or more café au lait spots > 5mm in children or > 15 mm in adults 2 or more neurofibromas or one plexiform neurofibroma Axillary or inguinal freckles Optic glioma 1 or more Lisch nodules (iris hamartomas) First degree relative with NFI

Neurofibromatosis I: 

Neurofibromatosis I Prevalence: 1/5000 to 1/3000 New mutations account for about 25 % Large gene on 17q11.2 affected Gene, Neurofibromin, affected by very numerous mutations Homologous to GTP binding regulatory proteins; thought to act as growth suppresser Neurofibromas have been shown to harbor mutations of the originally normal NF I gene. Loss of heterozygosity from somatic mutation of normal allele appears to be a major cause of tumor development Molecular test can detect neurofibromin abnormalities in about 70% of patients

Somatic mutations as the basis for neurofibroma formation: 

Somatic mutations as the basis for neurofibroma formation The normal appearing areas of skin are heterozygous for an NF1 mutation to begin with Mutation occurs in the previously normal NF1 gene in cell ‘M’ Mutation is propagated in ‘M’s offspring which form a neurofibroma Neurofibromatosis is really a recessive disease at the cellular level

Neurofibromatosis I: 

Neurofibromatosis I Complications include: Acoustic neuromas Cerebral malignancies and meningiomas Malignant degeneration of neurofibromas (5% lifetime risk) Painful and debilitating compressions of nerve roots, nerves and spinal cord Disfigurement Often accelerated growth and appearance of neurofibromas during pregnancy

Neurofibromatosis I: 

Neurofibromatosis I

Charcot-Marie-Tooth disease(s): 

Charcot-Marie-Tooth disease(s) Clinical features:Distal sensory and motor neuropathy, ‘Stork leg’ and pes cavus Onset: Childhood to adult Inheritance: Autosomal dominant Chromosome: 17p11: CMTIA, 1q22: CMTIB myelin protein P0, CMTX:Xq13 Connexin-32 gene Mutation: Duplication of 1.5 Megabase region that includes PMP22 (Point mutations in PMP22 cause recessive Dejerine-Sottas disease) Gene affected: Peripheral myelin protein-22 gene, encodes cytoplasmic Schwann cell protein Testing: Prolonged Nerve conductions, Southern blot test

Gene dosage (number) is important: 

Gene dosage (number) is important Null aka knockout (total absence of gene product) PMP22 mice have severe peripheral neuropathy One copy (hemizygous) of PMP22: HNPP Two copies of PMP22: Normal Three copies of PMP22: CMT1A Four copies of PMP22: Very severe demyelinating peripheral neuropathy

Hereditary neuropathy with predisposition to pressure palsies (HNPP): 

Clinical features: Self descriptive, especially peroneal palsy after kneeling Inheritance: Autosomal dominant Mutation: Reciprocal of CMTIA, i.e. deletion of 1.5 Mbase region duplicated in CMTIA Testing: EMG/NCV, gene test Hereditary neuropathy with predisposition to pressure palsies (HNPP)

CMT1A locus: 

CMT1A locus

Locus heterogeneity for CMT1: 

Locus heterogeneity for CMT1 CMT1A: 17p11: Duplication of region that includes PMP22 CMT1B: 1q22: Mutations of myelin protein zero (MPZ) CMT1C: 10q21: Mutations of EGR2, aka KROX20 CMT1D: 2p21: Mutations of Sox11 CMTXA: Xq13: Mutations of connexin 32 gene (a gap junction gene expressed in Schwann cells)

Concluding thoughts: 

Concluding thoughts Though rare, genetic diseases must be recognized in order to provide the most effective available treatments, including preventative therapies Recognition is important in order to educate and counsel families with or at risk for hereditary disorders Definitive diagnosis is essential before new treatments can be prescribed Insights into treating more common multifactorial diseases will likely result from understanding these ‘accidents of nature’

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