The sphingolipidoses are the most board-tested category of lysosomal storage diseases. All are autosomal recessive except Fabry disease (X-linked recessive).

Sphingolipidoses Overview Table

Cherry-Red Spot Diseases

• The cherry-red spot represents the normal fovea surrounded by lipid-laden, pale-appearing ganglion cells
• Mnemonic — “TaSNiGS”:
  • Tay-Sachs
  • Sandhoff
  • Niemann-Pick A
  • GM1 gangliosidosis
  • Sialidosis (neuraminidase deficiency)
• Also seen in central retinal artery occlusion (CRAO) — different mechanism (ischemic, not storage)

Tay-Sachs Disease

• Enzyme: hexosaminidase A deficiency
• Inheritance: AR; carrier frequency 1/30 in Ashkenazi Jewish population
• Onset: 3–6 months — developmental regression, exaggerated startle response (hyperacusis)
• Exam: cherry-red spot on fundoscopy, progressive hypotonia → spasticity, seizures, blindness, macrocephaly
• Key distinction: NO hepatosplenomegaly (GM2 accumulates in neurons only, not viscera)
• Pathology: neuronal swelling with membranous cytoplasmic bodies on EM
• Prognosis: death by age 3–5 years; no specific treatment

Gaucher Disease

• Enzyme: glucocerebrosidase (GBA) deficiency
• Most common lysosomal storage disease
• Pathology: Gaucher cells — macrophages with “crumpled tissue paper” or “wrinkled paper” cytoplasm

Gaucher Disease Types

Fabry Disease

• Enzyme: alpha-galactosidase A deficiency
• Inheritance: X-linked recessive — the only X-linked sphingolipidosis
• Accumulated substrate: globotriaosylceramide (Gb3)
• Neurologic: painful acroparesthesias (burning pain in hands/feet, triggered by heat/exercise), small fiber neuropathy, stroke (young adults)
• Dermatologic: angiokeratomas (dark red papules, classically in “bathing trunk” distribution)
• Ophthalmologic: corneal verticillata (whorl-like corneal deposits)
• Renal: progressive nephropathy → renal failure (leading cause of death)
• Cardiac: left ventricular hypertrophy, arrhythmias, cardiomyopathy
• Treatment: enzyme replacement therapy (agalsidase alfa or agalsidase beta); oral chaperone therapy (migalastat) for amenable mutations
• Female carriers can be symptomatic due to random X-inactivation (lyonization)

Niemann-Pick Type C

• Gene: NPC1 (95%) or NPC2 — intracellular cholesterol transport defect (NOT a sphingomyelinase deficiency)
• Presentation: childhood-onset progressive ataxia, dystonia, cognitive decline
• Hallmark: vertical supranuclear gaze palsy (initially downgaze, then upgaze)
• Other features: gelastic cataplexy, neonatal cholestasis, hepatosplenomegaly
• Diagnosis: filipin staining of skin fibroblasts, oxysterol biomarkers
• Treatment: miglustat (substrate reduction therapy)

Group of lysosomal storage diseases caused by defective degradation of glycosaminoglycans (GAGs). All are autosomal recessive except MPS II (Hunter) — X-linked recessive.

MPS Overview Table

• All MPS have corneal clouding EXCEPT Hunter (MPS II)
• Hunter is the only X-linked MPS — “Hunters need to see (clear corneas) and are X-linked”
• Diagnosis: elevated urinary GAGs + specific enzyme assay
• Treatment: enzyme replacement therapy and/or hematopoietic stem cell transplantation (MPS I)

Group of neurodegenerative disorders characterized by accumulation of autofluorescent lipopigment (ceroid-lipofuscin) in neurons and other cells. All are autosomal recessive.

NCL Types

• Common features: progressive seizures, visual loss, cognitive decline, motor deterioration → early death
• Diagnosis: enzyme assay (CLN1, CLN2), genetic testing, skin/conjunctival biopsy showing autofluorescent lipopigment
• Treatment: cerliponase alfa (intracerebroventricular ERT for CLN2)

Key GSDs Table

Pompe Disease — Key Details

• Infantile-onset: massive cardiomegaly, generalized hypotonia, feeding difficulty, tongue enlargement; death by age 1–2 without treatment
• Late-onset: progressive proximal myopathy + early respiratory failure (diaphragmatic weakness — often out of proportion to limb weakness)
• Diagnosis: GAA enzyme activity in dried blood spot or leukocytes; acid phosphatase elevated; muscle biopsy shows vacuolar myopathy with glycogen
• Treatment: enzyme replacement therapy (alglucosidase alfa) — improves survival in infantile form

McArdle Disease — Key Details

• Exercise intolerance with myalgia and cramping during intense anaerobic exercise
• Second-wind phenomenon: symptoms improve after brief rest and resumption of exercise (switch to fatty acid oxidation)
• Forearm exercise test: no rise in venous lactate (pathognomonic), with exaggerated ammonia rise
• Risk of rhabdomyolysis and myoglobinuria with strenuous exercise

Amino Acid Disorders Overview Table

Phenylketonuria (PKU)

• Most common amino acid disorder (~1/10,000)
• Deficient conversion of phenylalanine → tyrosine
• Untreated: severe intellectual disability, seizures, microcephaly, hyperactivity
• Fair phenotype: reduced melanin synthesis (tyrosine is a melanin precursor)
• Treatment: phenylalanine-restricted diet (lifelong); sapropterin (BH4 cofactor) for responsive patients
• Maternal PKU: uncontrolled maternal Phe levels → microcephaly, cardiac defects, intellectual disability in offspring (even if fetus does not have PKU)

Homocystinuria

• Lens subluxation: downward and inward (vs. Marfan → upward and temporal)
• Vascular: arterial and venous thromboembolism, stroke at a young age
• Skeletal: tall, thin habitus, arachnodactyly, pectus excavatum, scoliosis, osteoporosis
• Neurologic: intellectual disability, seizures, psychiatric disturbance
• Treatment: B6 (pyridoxine) — ~50% of patients are B6-responsive; also folate, B12, betaine, methionine-restricted diet

• Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder
• Inheritance: X-linked recessive (only X-linked UCD; all others are AR)
• Pathophysiology: impaired conversion of ammonia to urea → hyperammonemia

Clinical Presentation

• Neonatal: poor feeding, vomiting, lethargy → seizures → coma (within first few days of life)
• Late-onset: episodic encephalopathy triggered by protein load, illness, or catabolic stress
• Lab findings: elevated ammonia, elevated glutamine, low BUN, respiratory alkalosis (early) → metabolic crisis
• Specific to OTC: elevated urinary orotic acid (distinguishes from carbamoyl phosphate synthetase I deficiency)

Diagnosis and Treatment

• MRS (MR spectroscopy): elevated glutamine peak — hallmark of hyperammonemia
• MRI: diffuse cerebral edema in acute crisis; chronic → cortical atrophy
• Treatment:
  • Acute: IV sodium benzoate + sodium phenylacetate (nitrogen scavengers), arginine, hemodialysis if severe
  • Chronic: protein restriction, sodium phenylbutyrate (oral nitrogen scavenger), arginine/citrulline supplementation
  • Definitive: liver transplantation

• Gene: ATP7B (chromosome 13q14.3)
• Inheritance: autosomal recessive
• Pathophysiology: defective biliary copper excretion → copper accumulation in liver, brain (basal ganglia), cornea, kidneys
• Onset: typically age 5–40 years

Clinical Features

Neurologic

• Dystonia (most common neurologic finding)
• Wing-beating tremor (coarse, postural)
• Dysarthria, drooling
• Parkinsonism (rigidity, bradykinesia)
• Cerebellar signs (ataxia)
• Psychiatric: personality changes, depression, psychosis — may precede neurologic symptoms by years

Hepatic

• Acute hepatitis, chronic hepatitis, cirrhosis
• Fulminant hepatic failure (with Coombs-negative hemolytic anemia)

Ophthalmologic

• Kayser-Fleischer rings: copper deposition in Descemet membrane of cornea (greenish-brown ring at limbus)
• Present in >95% of patients with neurologic Wilson; ~50% of hepatic-only Wilson
• Best detected by slit-lamp examination
• Sunflower cataracts (less common)

Diagnostic Workup

Neuroimaging

• MRI brain: T2/FLAIR hyperintensity in the putamen, caudate, thalamus, midbrain, pons
• “Face of the giant panda” sign: characteristic T2 signal pattern in the midbrain (tegmentum hyperintense, surrounding structures dark)
• T1 hyperintensity in the basal ganglia (copper/manganese deposition)

Treatment

• Chelation: D-penicillamine (first-line, but many side effects) or trientine (better tolerated)
• Zinc: blocks intestinal copper absorption; used for maintenance and presymptomatic patients
• Liver transplantation: curative; indicated for fulminant hepatic failure or decompensated cirrhosis
• Treatment is lifelong — neurologic symptoms may initially worsen with penicillamine

Copper, Iron, and Purine Metabolism Disorders

Menkes vs. Wilson

PKAN (Pantothenate Kinase-Associated Neurodegeneration)

• Most common form of neurodegeneration with brain iron accumulation (NBIA)
• “Eye of the tiger” sign: T2 hypointensity in globus pallidus with central hyperintense spot — highly characteristic
• Progressive dystonia, spasticity, rigidity, dysarthria
• Pigmentary retinopathy, acanthocytosis on blood smear