LSDs Quick Flashcards

MPS I - Hurler Syndrome (Classic)

• Most Identifiable Symptom: Profound intellectual disability, coarse facial features, gibbus deformity (dysostosis multiplex). Presents before age 1.

• Genetic Inheritance & Gene: Autosomal Recessive. IDUA.

• Key Biochemical Finding: Deficient alpha-L-iduronidase. Elevated heparan & dermatan sulfate (GAGs).

• Treatment: ERT (laronidase/Aldurazyme). HSCT for classic form to slow CNS progression.

MPS I - Attenuated Forms (Hurler-Scheie, Scheie)

• Most Identifiable Symptom: Psychiatric illness/learning disabilities, significant skeletal disability (dysostosis multiplex). CNS involvement into 20s/30s

• Genetic Inheritance & Gene: Autosomal Recessive. IDUA.

• Key Biochemical Finding: Deficient alpha-L-iduronidase. Elevated GAGs.

• Treatment: ERT (laronidase/Aldurazyme).

MPS II - Hunter Syndrome

• Most Identifiable Symptom: Similar to Hurler but NO corneal clouding. Progressive intellectual disability, coarse features, death in teens/20s from cardiac disease.

• Genetic Inheritance & Gene: X-linked. IDS.

• Key Biochemical Finding: Deficient iduronate 2-sulfatase. Elevated heparan & dermatan sulfate.

• Treatment: ERT (idursulfase/Elaprase). Gene therapy in trials. HSCT mixed results clinically.

MPS III - Sanfilippo Syndrome

• Most Identifiable Symptom: Severe behavioral issues (hyperactivity, aggression), seizures, ataxia, developmental regression after normal early development. Death by early teens and twenties.

• Genetic Inheritance & Gene: Autosomal Recessive. SGSH (A), NAGLU (B), HGSNAT (C), GNS (D).

• Key Biochemical Finding: Enzyme deficiency depends on type. Elevated heparan sulfate.

• Treatment: Symptomatic only. ERT/gene therapy in trials.

MPS IV - Morquio Syndrome

• Most Identifiable Symptom: Severe skeletal dysplasia (kyphoscoliosis, short stature) with normal cognition.

• Genetic Inheritance & Gene: Autosomal Recessive. GALNS (A), GLB1 (B).

• Key Biochemical Finding: Enzyme deficiency (e.g., galactose-6-sulfate sulfatase for A). Elevated keratan & chondroitin sulfate.

• Treatment: ERT for Type A only (elosulfase alfa/Vimizin).

MPS VI - Maroteaux-Lamy Syndrome

• Most Identifiable Symptom: Severe skeletal manifestations, coarse facies, with normal cognition. Cardiopulmonary disease, absent or delayed puberty

• Genetic Inheritance & Gene: Autosomal Recessive. ARSB.

• Key Biochemical Finding: Deficient arylsulfatase B. Elevated dermatan sulfate.

• Treatment: ERT (galsulfase/Naglazyme).

MPS VII - Sly Syndrome

• Most Identifiable Symptom: Extremely variable; can present with hydrops fetalis. Also coarse facies, cardiac valve disease, ID

• Genetic Inheritance & Gene: Autosomal Recessive. GUSB.

• Key Biochemical Finding: Deficient beta-glucuronidase. Elevated heparan, dermatan, chondroitin sulfates.

• Treatment: Symptomatic. ERT available (vestronidase alfa/Mepsevii).

Tay-Sachs Disease

• Most Identifiable Symptom: Developmental regression, hypotonia, exaggerated startle, cherry red spot.

• Genetic Inheritance & Gene: Autosomal Recessive. HEXA.

• Key Biochemical Finding: Deficient beta-hexosaminidase A.

• Treatment: Symptomatic, death within the first 2-3 years of life.

Fabry Disease - Male Presentation

• Most Identifiable Symptom: Acroparasthesia (burning pain in hands/feet), angiokeratomas, hypohidrosis, corneal whorling. Onset 4-8 years. Death in 30s/40s.

• Genetic Inheritance & Gene: X-linked. GLA.

• Key Biochemical Finding: Deficient alpha-galactosidase A. Elevated GL3/lyso-GL3.

• Treatment: ERT (agalsidase beta/Fabrazyme). Chaperone therapy (migalastat/Galafold).

Fabry Disease - Female Presentation

• Most Identifiable Symptom: Variable. Can have acroparasthesias, heat intolerance, cardiac/renal disease, early strokes, GI issues. Onset often in teens.

• Genetic Inheritance & Gene: X-linked. GLA.

• Key Biochemical Finding: Deficient alpha-galactosidase A. Elevated GL3/lyso-GL3.

• Treatment: ERT (agalsidase beta/Fabrazyme). Chaperone therapy (migalastat/Galafold).

Gaucher Disease Type 1

• Most Identifiable Symptom: Hepatosplenomegaly, cytopenias, bone disease. No CNS involvement.

• Genetic Inheritance & Gene: Autosomal Recessive. GBA.

• Key Biochemical Finding: Deficient glucocerebrosidase. Elevated GL1/lyso-GL1.

• Treatment: ERT (e.g., imiglucerase/Cerezyme). SRT (eliglustat/Cerdelga).

Gaucher Disease Type 2 (Acute Neuronopathic)

• Most Identifiable Symptom: Bulbar signs (stridor, dysphagia), pyramidal signs (spasticity), rapid neurodegeneration. Death by 2-4 years.

• Genetic Inheritance & Gene: Autosomal Recessive. GBA.

• Key Biochemical Finding: Deficient glucocerebrosidase. Elevated GL1/lyso-GL1.

• Treatment: ERT is NOT approved. Symptomatic.

Gaucher Disease Type 3 (Subacute/Chronic Neuronopathic)

• Most Identifiable Symptom: Slower progression. Hepatosplenomegaly, seizures, dementia, ataxia. Onset childhood to adulthood.

• Genetic Inheritance & Gene: Autosomal Recessive. GBA.

• Key Biochemical Finding: Deficient glucocerebrosidase. Elevated GL1/lyso-GL1.

• Treatment: ERT IS approved. Symptomatic.

Gaucher Disease - Perinatal Lethal Form

• Most Identifiable Symptom: Hydrops fetalis, pancytopenia, arthrogryposis, colloid skin changes. Fetal demise or perinatal death.

• Genetic Inheritance & Gene: Autosomal Recessive. GBA.

• Key Biochemical Finding: Deficient glucocerebrosidase. Elevated GL1/lyso-GL1.

• Treatment: (Not applicable; lethal pre/neonatally).

Metachromatic Leukodystrophy (MLD)

• Most Identifiable Symptom: Cognitive decline/regression, spasticity, gait issues, demyelination on MRI. Infantile onset <30mo

  • Juvenile (3-16yr) and Late onset (>16yr) forms also observed.

• Genetic Inheritance & Gene: Autosomal Recessive. ARSA or PSAP.

• Key Biochemical Finding: Deficient arylsulfatase A.

• Treatment: Symptomatic. Early HSCT for late-juvenile/adult forms. Ex-vivo HSCT gene therapy (2024).

Krabbe Disease - Late Onset

• Symptom: After 12 months. Cognitive decline/regression, spasticity, gait issues, demyelination on MRI.

• Inheritance/Gene: Autosomal Recessive. GALC

• Biochemical Finding: galactocerebroside / Biomarker: psychosine

• Treatment: Symptomatic. Early HSCT for late-juvenile/adult forms. Ex-vivo HSCT gene therapy (2024).

Krabbe Disease - Infantile Onset

• Symptom: Before 12 months. Extreme irritability, feeding difficulties, hypotonia/spasticity, loss of milestones, progressive vision loss. Psychosine on NBS.

• Inheritance/Gene: Autosomal Recessive. GALC.

• Biochemical Finding: Deficient galactocerebrosidase. Elevated psychosine.

• Treatment: Symptomatic. HSCT before 14 days of life. Gene therapy in development.

Niemann-Pick Disease Type A (Acute Neuronopathic)

• Most Identifiable Symptom: Massive hepatosplenomegaly from 3 months, developmental delay, cherry red spot, death by age 3.

• Genetic Inheritance & Gene: Autosomal Recessive. SMPD1.

• Key Biochemical Finding: Deficient acid sphingomyelinase. Sphingomyelin accumulation.

• Treatment: ERT (olipudase alfa) is for non-CNS symptoms.

Niemann-Pick Disease Type B (Chronic Visceral)

• Most Identifiable Symptom: Juvenile onset. Gradual liver and pulmonary dysfunction. No CNS manifestations.

• Genetic Inheritance & Gene: Autosomal Recessive. SMPD1.

• Key Biochemical Finding: Deficient acid sphingomyelinase. Sphingomyelin accumulation.

• Treatment: ERT (olipudase alfa) for visceral symptoms.

Niemann-Pick Disease Type C

• Most Identifiable Symptom: Vertical supranuclear gaze palsy, ataxia, gelastic cataplexy, psychiatric problems.

• Genetic Inheritance & Gene: Autosomal Recessive. NPC1 or NPC2.

• Key Biochemical Finding: Cholesterol trafficking defect; abnormal oxysterol profile.

• Treatment: Miglustat (Zavesca) - approved in UK, not USA. Arimoclomol in trials.

Pompe Disease - Infantile Onset (IOPD)

• Most Identifiable Symptom: Severe hypotonia, hypertrophic cardiomyopathy, respiratory failure. Onset before 12 months.

• Genetic Inheritance & Gene: Autosomal Recessive. GAA.

• Key Biochemical Finding: Deficient acid alpha-glucosidase. Glycogen in lysosomes.

• Treatment: ERT (alglucosidase alfa/Lumizyme). Immunomodulation if CRIM-negative.

Pompe Disease - Late Onset (LOPD)

• Most Identifiable Symptom: Progressive muscle weakness, motor delay, elevated CK, risk for respiratory compromise. Onset after 12 months (or before without cardiomyopathy).

• Genetic Inheritance & Gene: Autosomal Recessive. GAA.

• Key Biochemical Finding: Deficient acid alpha-glucosidase. Glycogen in lysosomes.

• Treatment: ERT (alglucosidase alfa/Lumizyme).

Neuronal Ceroid Lipofuscinosis - CLN2 Disease

• Most Identifiable Symptom: Onset 2-4 years with intractable seizures and developmental regression.

• Genetic Inheritance & Gene: Autosomal Recessive. CLN2.

• Key Biochemical Finding: Accumulation of lipopigments.

• Treatment: ERT (cerliponase alfa/Brineura) - weekly intraventricular injection.

Neuronal Ceroid Lipofuscinosis - CLN3 Disease

• Most Identifiable Symptom: Onset 4-10 years with retinal degeneration, progressing to cognitive decline and seizures.

• Genetic Inheritance & Gene: Autosomal Recessive. CLN3.

• Key Biochemical Finding: Accumulation of lipopigments.

• Treatment: Symptomatic. Gene therapy for vision in trials.