Niemann-Pick Disease Overview

Incomplete Penetrance & Variable Expressivity

• Incomplete penetrance occurs when individuals inherit a mutant gene but remain phenotypically normal.
• Variable expressivity means the trait is observable in all carriers of a mutant gene but manifests differently among them (e.g., Neurofibromatosis type 1).
• Delayed age of onset is common in certain autosomal dominant diseases.
• Autosomal dominant diseases can involve regulation of complex metabolic pathways or key structural proteins like collagen.

Autosomal Recessive Disorders

• Genotype for autosomal recessive disorders is typically homozygous recessive (aa).
• Phenotype usually expressed only when both recessive alleles are inherited.
• Frequently involve enzyme proteins; males and females are equally affected.
• Siblings have a 25% chance of displaying the disease if both parents are carriers.
• Low frequency mutant genes often indicate consanguineous marriages.
• Expression of defects is generally uniform with complete penetrance, onset is often early, but they may remain clinically undetected.
• Commonly include inborn errors of metabolism.

X-Linked Disorders

• Genotype is influenced heavily by the X chromosome, can be dominant or recessive.
• Phenotypic expression can be complete, partial, or absent.
• Most sex-linked disorders are X-linked and typically recessive; males with mutations affecting Y-linked genes are usually infertile.
• Types of X-linked disorders include hemoglobinopathies (defects in globin structure), thalassemias (deficits in globin synthesis), and defects in structural proteins like collagen and dystrophin.

Genetically Determined Adverse Reactions to Drugs

• Pharmacogenetics studies how genetics influence response to medications.
• Certain enzyme deficiencies manifest only after drug exposure, significantly impacting drug sensitivity and adverse reactions (e.g., G6PD deficiency and primaquine leading to hemolytic anemia).

Disorders Associated with Defects in Structural Proteins

Marfan Syndrome

• Connective tissue disorder affecting skeleton, eyes, and cardiovascular system.
• Prevalence is about 1 in 5,000; 70-85% familial (autosomal dominant) and 15-30% arise from new mutations.
• Clinical signs include a characteristic cherry-red spot in the macula of the eye, which appears early in the disease course.

Niemann-Pick Disease Types A and B

• Lysosomal disorder characterized by sphingomyelin accumulation due to sphingomyelinase deficiency.
• Most often diagnosed in Ashkenazi Jews; primarily an autosomal recessive condition.
• Pathology includes vacuolation of neurons and the presence of zebra bodies.
• Type A is a severe form with early neurologic involvement; Type B has organomegaly but minimal CNS impact.

Trisomy Disorders

• Trisomy 21 (Down syndrome) results from meiotic nondisjunction, leading to overexpression of genes on chromosome 21, including APP.
• Clinical features include distinct facial characteristics and various organ system abnormalities.
• Trisomy 18 (Edwards syndrome) and Trisomy 13 (Patau syndrome) are more severe, with infants rarely surviving beyond the first year.

Chromosome 22q11.2 Deletion Syndrome

• Results from deletion on chromosome 22, affecting multiple developmental processes.
• Prevalence is around 1 in 4,000 births.
• Clinical manifestations include congenital heart defects, cleft palate, facial dysmorphism, and immunodeficiencies.
• Disorders stemming from this deletion can include DiGeorge syndrome and velocardiofacial syndrome.

Genomic Imprinting

• Imprinting refers to the differential expression of paternal and maternal alleles.
• Maternal imprinting silences the maternal allele; paternal imprinting silences the paternal allele.
• Illustrated by Prader-Willi syndrome (paternal deletion) and Angelman syndrome (maternal deletion).
• Prader-Willi syndrome is characterized by obesity and intellectual disability, while Angelman syndrome features microcephaly and ataxia.
• Three mechanisms of genomic imprinting include chromosomal deletions that lead to syndromes depending on which parent's allele is affected.