Neurological Diseases

Neurofibromatosis 1

• Single gene disorder

• Gene is Neurofibromin (NF1)

• Mutations inactivate tumor suppression function

Neurofibromatosis 1 Inheritance

• Autosomal dominant

Neurofibromatosis 1 S/S

• Hundreds of tumors that protrude through the skin

• Light brown skin spots

Neurofibromatosis 2

• Single gene disorder

• Mutations in the Merlin gene; NF2

Neurofibromatosis 2 Inheritance

• Autosomal dominant

Neurofibromatosis 2 S/S

• Morbidity and mortality due to vestibular schwannomas

Neurofibromatosis 1 Vs. 2

Lysosomal Storage Disorders

• Single gene disorder

• Deficiencies in the (Lysozymes) enzymes responsible for degradation of these substrates result in their accumulation

• 2 Major classes…

  • Mucopolysaccharidoses = Degrade glycosaminoglycan (GAG) a constituent of extracellular matrix, joint fluid, and connective tissue

  • Sphingolipidoses = Complex lipids and major component of cell membranes

Mucopolysaccharidoses

• Single gene disorders

• 14 known types that affects degradation of Glycosaminoglycans (GAGs)

  • Heparan sulfate

  • Dermatan sulfate

  • GAGs = Important constituents in connective tissue

Mucopolysaccharidoses Inheritance

• Autosomal recessive

Mucopolysaccharidoses S/S

• Coarse facies, thick skin, corneal clouding and organomegaly, intellectual disability, growth deficiencies, skeletal dysplasias

Sphingolipidosis (Lipid Storage Diseases)

• Single gene disorder

• Inability to degrade sphingolipid resulting in the progressive deposition of lipid or glycolipid I in the brain, liver, and spleen

  • Can lead to…

    • Fabry disease

    • Gaucher disease

    • Tay-Sachs disease

Fabry Disease

• Musculoskeletal disorder

  • Sphingolipidosis

• Caused by a deficiency of the enzyme a-galactosidase

  • Encoded by the GLA gene leading to progressive deposits in the lysosomes

Fabry Disease Inheritance

• X-Linked recessive

Fabry Disease S/S

• Unpleasant pain in extremities

• Angiokeratomas

• Hypohydrosis

• Corneal/Lens opacities

• Hematuria

• Renal failure

• Hypertrophic cardiomyopathy

Gaucher Disease

• Musculoskeletal disorder

  • Sphingolipidosis

• Type I

  • Pain in limbs, joints, or trunk

  • Febrile episodes

  • Pathological fractures

• Type II

  • Hepatosplenomegaly

  • Developmental/Neurological deterioration

Gaucher Disease Inheritance

• Autosomal recessive

Tay-Sachs Disease

• Musculoskeletal disorder

  • Sphingolipidosis

• Caused by mutation of HEXA gene and enzyme deficiency of Hexosaminidase A

Tay-Sachs Disease S/S

• Hypotonia, difficulty feeding, apathy, motor weakness, developmental regression, intellectual disability

• Cherry-red spot on the retina

• Neurological deterioration, seizures, decerebrate rigidity, deafness

Tay-Sachs Disease Inheritance

• Autosomal recessive

Huntington Disease

• Caused by HD Repeat found in the first exon of the gene and expansion of CAG triplet repeats

  • Number of CAG repeats normally present in Huntington gene is 10 - 26

Huntington Disease Inheritance

• Autosomal dominant

Huntington Disease Anticipation

• Larger expansion/Earlier onset of disease with more severe symptoms

Huntington Disease S/S

• Progressive

• Motor, psychiatric, cognitive issues

Alzheimer Disease

• Disease of the brain

• Familial Alzheimer Disease (FAD)

  • Early onset = Distinguishable clinically and neurologically

• Caused by mutations in APP, PSEN1, or PSEN2

Alzheimer Disease Inheritance

• Autosomal dominant

Alzheimer Disease Amyloid Plaques & Tangles

• Amyloid Plaques = Protein fragments that accumulate to form hard, insoluble plaques

• Tangles = Abnormal tubules collapse

Alzheimer Disease S/S

• Shrinkage of brain tissue

• Memory fade

• Judgement decline

• Increased emotional lability

• Language impairment

APP Gene

• Mutation in APP gene forms amyloid plaques

PSEN1 & PSEN2

• PSEN1 = Codes for protein; Impaired mitochondrial function, formation of reactive oxygen species, and increased vulnerability to apoptosis

• PSEN2

APOE

• Apolipoprotein E Gene

  • Susceptibility gene

• Known factor for cardiovascular disease and predisposes to late onset Alzheimer’s Disease

APOE Testing

• APOE Genotype used to confirm diagnosis