Term
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Definition
Foamy macrophages; “sea-blue” histocytes; sphingomyelin
**Lysosomal Storage Diseases |
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Term
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Definition
Acid maltase deficiency
**Lysosomal Storage Diseases |
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Term
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Definition
Clinical Manifestations
-Onset typically within first 6 months
-Extreme irritability and hypersensitivity to external stimuli
-Feeding difficulties
-Spasticity
-Progressive neurologic deterioration
-Cortical blindness with optic atrophy
-Deafness
-Usually fatal by 2 years of age
Molecular Basis of Disease
-GALC gene codes for galactosylceramidase (galactocerebrosidase) which degrades galactocerebroside to ceramide and galactose
-Mutations cause deficient enzyme activity resulting in accumulation of enzyme substrates and early destruction of myelin-forming oligodendroglia
Laboratory
-Deficient galactosylceramide beta galactosidase activity in leukocytes or cultured fibroblasts |
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Term
| Metachromatic Leukodystrophy |
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Definition
•Chromosome and Gene Location
–22q13.31–qter, autosomal recessive
•Clinical Manifestations
–Late infantile (50–60% of cases)
•Onset typically between 1 and 2 years
•Hypotonia, weakness, clumsiness, frequent falls, toe walking, inability to stand
•Progressive neurologic deterioration
•Increased muscle tone
•Blindness
•Death typically occurs approximately 5 years after onset of symptoms
–Juvenile (20–30% of cases)
•Onset typically between 4 and 14 years
•Decline in school performance, behavioral problems
•Clumsiness, gait problems
•Slurred speech
•Seizures
•Death typically by 20 years of age
–Adult (15–20% of cases)
•Onset typically after puberty and into sixth decade of life
•Problems in school or job performance, personality changes
•Weakness, loss of coordination, peripheral neuropathy
•Seizures
•Duration of disease can range from few years to several decades before patient reaches a vegetative state, and ultimately, death
•Molecular Basis of Disease
–ARSA (arylsulfatase A) gene mutations lead to deficiency in the enzymatic hydrolysis of sulfatide and subsequent accumulation of sulfatideswithin lysosomes
•Laboratory
–Deficient arylsulfatase A enzyme activity in leukocytes or cultured fibroblasts
–Presence of individuals with pseudodeficiency (unaffected individuals whose ARSA activity in leukocytes is 5–20% of controls)
–Metachromatic lipid deposits in a nerve or brain biopsy
–Increased urinary sulfatide excretion |
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Term
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Definition
•Chromosome and Gene Location
–Xq22.1
•Clinical Manifestations
–Onset typically in childhood or adolescence
–Pain in distal extremities (acroparesthesias)
–Fever due to hypohidrosis (reduced sweating)
–Corneal opacities
–Angiokeratomas (usually bathing suit distribution)
–Proteinuria; end stage renal disease typically occurs in the third to fifth decade
–Cardiovascular disease
–Carrier females usually asymptomatic, but can be as severely affected as males or have an attenuated form of disease due to random X-inactivation
•Molecular Basis of Disease
–GLA gene codes for alpha galactosidaseA involved in degradation of glycosphingolipids
–Mutations in GLA gene result in accumulation of globotriaoslyceramide (Gb3) and other glycosphingolipidsin body fluids and lysosomes of cells of various organs
•Laboratory
–Deficient alpha-galactosidaseA activity in leukocytes, tears, cultured fibroblasts, plasma, or serum
•Treatment
–Enzyme replacement therapy
–Renal dialysis and transplantation |
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Term
| Lysosomal storage disorders |
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Definition
•Mucopolysaccharidoses
•Sphingolipidoses
–GM2 Gangliosidoses
•Tay–Sachs Disease
•Sandhoff Disease
–Niemann–Pick Disease
–GaucherDisease
–Krabbe Disease
–Metachromatic Leukodystrophy
–Fabry Disease |
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Term
| Spinal Muscular Atrophy (SMA) |
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Definition
•Molecular Basis of Disease
–Survival Motor Neuron (SMN1) is homozygously deleted in nearly all of type I and II and about 80% of type III Spinal Muscular Atrophy (SMA)
–2–5% of type I SMA caused by compound heterozygosity for SMN1 deletion and point mutation
–Presence of three or more copies of SMN2 (gene just adjacent to SMN1) associated with milder SMA phenotype in individuals with two SMN1 deletions and/or point mutations |
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Term
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Definition
•Dyskeratosiscongenita
•Hoyeraal-Hreidarsson syndrome
•Revesz syndrome |
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Term
| Myotonic Dystrophy Type 1 |
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Definition
•Wide phenotypic range and age of onset from severely affected infants (congenital DM1) to classically affected adults (classic DM1) to minimally symptomatic elderly individuals (mild DM1)
•Myotonia(sustained muscle contraction), muscle wasting, facial weakness
•Cataracts
•Hypogonadism
•Frontal balding
•Cardiac conduction disturbances
•Diabetes mellitus (5%)
•Swallowing and speech disability
•Neonatal hypotonia and delayed motor development
**trinucleotide repeat disease |
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Term
| Trinucleotide repeat disease |
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Definition
-Huntington Disease
-Friedrich Ataxia
-Fragile X syndrome
-Myotonic Dystrophy Type 1 |
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Term
| Polycystic Kidney Disease |
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Definition
•Autosomal dominant; genetic heterogeneity; PKD1 or PKD2 mutations
•Cysts of kidneys, liver, pancreas, ovaries, spleen; berry aneurysms; mitral valve prolapse
•Two-hit hypothesis for cyst development |
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Term
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Definition
•Absence of parasympathetic ganglia cells in submucosa and myenteric plexus of intestine (colonic aganglionosis); short-segment or long-segment disease
•Genetic heterogeneity; incomplete penetrance; variable expressivity
•Constipation and abdominal distention |
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Term
| Familial Hypercholesterolemia |
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Definition
•Mutation in LDL receptor; autosomal dominant
•Environmental modification; variable expression
•Early onset homozygous; later onset heterozygous
•Hypercholesterolemia, atherosclerosis, xanthomas |
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Term
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Definition
•Multiple congenital anomalies
–Ocular coloboma
–Choanalatresia
–Cranial nerve anomalies
–Ear anomalies
–Heart defects
–Tracheo-esophageal abnormalities
–Growth retardation
–Genital abnormalities
•Defect of CHD7 gene at chromsome 8p12; chromodomainhelicase DNA-binding gene
• |
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Term
| Glucose-6-Phosphate Dehydrogenase Deficiency |
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Definition
•X-linked; predisposition to hemolysis, particularly following oxidant drugs (such as sulfonamides), toxins (such as fava beans), or infection; Heinz bodies (denatured hemoglobin)
•Neonatal jaundice or hemolytic anemia
•Heterozygote advantage (resistance to malaria)
•Symptomatic female carriers due to skewed Lyonization
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Term
| von Hippel-Lindau Disease |
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Definition
•Chromosome and Gene Location
–3p25–26 (VHL), autosomal dominant
•Clinical Manifestations
–Retinal hemangioblastomas (45–59%)
–Cerebellar hemangioma (44–72%)
–Spinal hemangiomas (13–59%)
–Pheochromocytoma(15%)
–Pancreatic cystic disease
–Cystadenomaof the epididymis (10–26%)
–Renal cysts (60%)
–Renal cell carcinoma
•Molecular Basis of Disease
–VHLis a tumor suppressor gene, whose gene product functions to negatively regulate transcription
•Treatment/Surveillance
–For hemangioblastomas of eye, treatment with laser photocoagulation
–For symptomatic hemangioblastomasof the central nervous system, surgical removal
–Nephron-sparing surgery is used for renal tumors greater than 3 cm in size
–Screening recommendations include:
•Annual physical exam with neurologic evaluation for signs of cerebellar or spinal cord lesions
•Annual ophthalmologic examination, blood pressure check, red blood cell count for polycythemia, urinalysis
•Baseline MRI imaging of CNS and cord at age 11, with repeat studies guided by clinical symptoms
•Annual imaging no later than age 16 for kidneys and pancreas by CT and/or ultrasound |
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Term
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Definition
•Chromosome and Gene Location
–19p13.3 (STK11), autosomal dominant
•Clinical Manifestations
–Numerous pigmented spots found on lips and buccalmucosa (more rarely on face, forearms hands, feet, and perianal area)
–Multiple gastrointestinal hamartomatous polyps found in the jejunum (malignant transformation not common)
–Risk of any malignancy estimated as 67–85% by age 70 years
–Most reported cancers are breast or gastrointestinal tract in patients who are under 40 years
–Also cancers of the cervix, ovaries, testis, pancreas, lung, uterus
•Molecular Basis of Disease
–Mutations in the serine threonine kinase, STK11
•Laboratory
–Polyps have a unique cellular morphology imparting branching tree-like appearance of mucosa with interdigitating smooth muscle
•Treatment/Surveillance
–Removal of polyps if feasible to prevent small bowel intussusception
–Screening includes:
•Upper and lower GI endoscopy and small bowel X-rays at age 10.
•Regular breast examination and imaging starting age 25–35 years
•Gynecologic screening with ultrasound starting at age 20
•Testicular examination annually starting at age 10 |
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