2.6 Glycogen, Lipid Storage & Amino Acid Disorders

Glycogen Storage Diseases (GSDs)

Inherited enzyme deficiencies that impair glycogen synthesis or degradation, accumulating abnormal glycogen in the liver, skeletal muscle, or heart.

                               Glycogen Degradation Pathways
                Glycogen ──(Muscle Glycogen Phosphorylase)──> Glucose-1-Phosphate [McArdle Disease]
                   │
                   ├──(Lysosomal Acid Alpha-Glucosidase)───> Free Glucose [Pompe Disease]
                   │
                   └──(Hepatic Glycogenolysis)─────────────> Glucose-6-Phosphate
                                                                   │
                                                                   ▼ (Glucose-6-Phosphatase)
                                                          Free Glucose in Blood [Von Gierke Disease]

Type I: Von Gierke Disease (GSD Type Ia)

• Enzyme Defect: Autosomal recessive deficiency of glucose-6-phosphatase, which dephosphorylates glucose-6-phosphate to free glucose in the endoplasmic reticulum of hepatocytes and renal tubular cells.
• Pathophysiology: Both glycogenolysis and gluconeogenesis are completely blocked. The liver cannot release free glucose into the systemic circulation.
• Clinical & Laboratory Manifestations:
  • Severe Fasting Hypoglycaemia: Profound lethargy, seizures, and sweating within 2-4 hours of fasting.
  • Massive Hepatomegaly & Renomegaly: Due to excessive glycogen storage; spleen is normal.
  • Doll-Like / Cherubic Facies: Chubby cheeks caused by subcutaneous adipose deposition.
  • Lactic Acidosis: Glucose-6-phosphate cannot form glucose and is shunted into glycolysis, generating massive amounts of pyruvate and lactate.
  • Hyperuricaemia & Gout: Lactic acid competitively inhibits urate secretion at the organic anion transporter (URAT1) in renal tubules, causing severe secondary hyperuricaemia and gout.
  • Hyperlipidaemia: Shunting into glycerol-3-phosphate and acetyl-CoA causes striking hypertriglyceridaemia, eruptive xanthomas, and hepatic adenomas.
  • Glucagon Challenge Test: Administration of glucagon fails to increase blood glucose and exacerbates lactic acidosis.
• Management: Frequent feeds, overnight continuous nasogastric glucose infusion or oral uncooked cornstarch.

Type II: Pompe Disease (GSD Type II)

• Enzyme Defect: Autosomal recessive deficiency of lysosomal acid alpha-1,4-glucosidase (acid maltase).
• Pathophysiology: Glycogen cannot be degraded within secondary lysosomes, engorging lysosomes in skeletal muscle, cardiac myocytes, and motor neurons. Cytosolic glycogenolysis is entirely intact, so blood glucose and hepatic function are completely normal.
• Clinical Features: Infantile-onset form presents with massive cardiomegaly, severe hypertrophic cardiomyopathy, profound generalized hypotonia ("floppy infant"), macroglossia, respiratory distress, and death before age 1 from heart failure. Adult-onset form presents with progressive proximal myopathy and early diaphragmatic weakness.
• Management: Recombinant human enzyme replacement therapy (alglucosidase alfa).

Type V: McArdle Disease (GSD Type V)

• Enzyme Defect: Autosomal recessive deficiency of skeletal muscle glycogen phosphorylase (myophosphorylase). Hepatic phosphorylase is normal, so blood glucose is unaffected.
• Pathophysiology: Skeletal myocytes cannot break down intracellular glycogen during anaerobic exertion, depriving working muscle of glucose-6-phosphate for anaerobic glycolysis.
• Clinical Manifestations: Painful muscle cramping, exercise intolerance, and fatigue induced by brief bouts of high-intensity anaerobic exercise (sprinting, lifting weights). Rhabdomyolysis causes myoglobinuria (cola-colored urine; dipstick positive for blood, negative for intact RBCs on microscopy), risking acute tubular necrosis.
• "Second-Wind" Phenomenon: After 8-10 minutes of rest or slow exertion, exercise tolerance dramatically improves because hepatic delivery of circulating blood glucose and free fatty acids reaches working muscle, restoring aerobic ATP production.
• Diagnostic Ischemic Forearm Test: Failure of venous blood lactate to rise following ischemic forearm exercise, with a normal or exaggerated rise in blood ammonia.

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Lipid Storage Diseases: The Sphingolipidoses

Sphingolipidoses are lysosomal storage disorders characterized by the progressive accumulation of unhydrolysed gangliosides, cerebrosides, or sphingomyelin within cellular lysosomes.

Gaucher Disease: Detailed Clinical Features

• Most prevalent lysosomal storage disease, particularly high frequency among Ashkenazi Jewish populations.
• Type 1 (Non-Neuronopathic, 95% of cases): Macrophages engulf senescent erythrocytes and leukocytes but cannot degrade glucocerebroside, transforming into Gaucher cells (engorged macrophages with striated cytoplasm resembling "wrinkled tissue paper" or "crumpled silk").
• Clinical Triad: (1) Hepatosplenomegaly (massive splenomegaly causing hypersplenism), (2) Pancytopenia (thrombocytopenia leading to bruising/epistaxis, normocytic anaemia), and (3) Skeletal pathology (recurrent severe "bone crises" from bone marrow infiltration, osteopenia, osteonecrosis/avascular necrosis of the femoral heads, and pathognomonic Erlenmeyer flask deformities on plain radiographs of the distal femur).
• Management: Recombinant enzyme replacement therapy (imiglucerase, velaglucerase alfa) or substrate reduction therapy (eliglustat, miglustat).

Fabry Disease: Detailed Clinical Features

• X-linked recessive disorder caused by inactivating mutations in the GLA gene. Globotriaosylceramide (Gb3) accumulates in vascular endothelial cells, smooth muscle, renal podocytes, and cardiomyocytes.
• Early Manifestations (Childhood / Adolescence):
  • Acroparaesthesias: Agonizing, burning pain and dysaesthesias in the hands and feet, precipitated by fever, hot weather, exercise, or fatigue.
  • Angiokeratomas: Clustered, punctate, dark red to purple, non-blanching maculopapular vascular lesions located symmetrically in a "bathing trunk" distribution (umbilicus, groin, buttocks, upper thighs).
  • Hypohidrosis / Anhidrosis: Inability to sweat normally, predisposing to heat intolerance.
  • Cornea Verticillata: Whorl-like corneal opacities seen on slit-lamp biomicroscopy without visual impairment.
• Late Manifestations (Adulthood, 30s-50s):
  • Renal: Progressive proteinuria, glomerulosclerosis, and end-stage renal disease (ESRD).
  • Cardiac: Concentric left ventricular hypertrophy, conduction abnormalities, and early myocardial infarction.
  • Cerebrovascular: Premature ischaemic stroke and transient ischaemic attacks.
• Management: Recombinant enzyme replacement (agalsidase alfa / beta) or pharmacological chaperone therapy (migalastat for amenable missense mutations).

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Disorders of Amino Acid Metabolism

                      Phenylalanine and Tyrosine Catabolism Pathways
  Phenylalanine ──(Phenylalanine Hydroxylase / BH4)──> Tyrosine ──> DOPA ──> Melanin & Catecholamines
        │                                                 │
        └───[Block: PKU]                                  ▼
                                                Homogentisic Acid
                                                          │
                                                          └───[Block: Alkaptonuria (HGAO)]
                                                          ▼
                                                Maleylacetoacetate ──> Fumarate + Acetoacetate

Phenylketonuria (PKU)

• Enzyme Defect: Autosomal recessive deficiency of phenylalanine hydroxylase (PAH) on chromosome 12q23, which converts phenylalanine to tyrosine using tetrahydrobiopterin (BH4) as an essential cofactor. Rare variants (~2%) stem from dihydropteridine reductase (DHPR) deficiency or defective BH4 synthesis.
• Pathophysiology: Unmetabolised phenylalanine accumulates to toxic concentrations in plasma and tissues, shunting into transamination products: phenylpyruvate, phenyllactate, and phenylacetate.
• Clinical Manifestations (Untreated):
  • Severe, irreversible intellectual disability and microcephaly.
  • Seizures and hyperreflexia.
  • Hypopigmentation: Fair skin, blonde hair, and blue eyes (phenylalanine competitively inhibits tyrosinase, impairing melanin synthesis from tyrosine).
  • Eczematous skin rash.
  • Musty / Mousy Body Odour: Imparted by phenylacetate excreted in sweat and urine.
• Diagnosis: Universal newborn dried blood spot screening (tandem mass spectrometry) at day 5 of life.
• Management: Lifelong dietary phenylalanine restriction, synthetic amino acid formulas enriched with tyrosine (which becomes an essential amino acid), and sapropterin (BH4 analogue) in responsive variants.
• Maternal PKU Syndrome: A woman with PKU who discontinues dietary restriction before or during pregnancy exposes her developing fetus to high maternal phenylalanine (which readily crosses the placenta). Phenylalanine acts as a potent teratogen, producing microcephaly, congenital heart defects (tetralogy of Fallot, VSD), intellectual disability, and intrauterine growth restriction, regardless of the fetus's genotype.

Homocystinuria

• Enzyme Defect: Autosomal recessive deficiency of cystathionine beta-synthase (CBS) on chromosome 21q22, which condenses homocysteine with serine to form cystathionine. Requires pyridoxal 5'-phosphate (vitamin B6) as a cofactor.
• Pathophysiology: Severe accumulation of homocysteine and methionine in plasma and urine. Excess homocysteine reacts with reactive sulfhydryl groups, disrupting disulfide bonds and cross-linking in collagen and fibrillin-1.
• Clinical Hallmarks:
  • Marfanoid Habitus: Tall stature, slender build, arachnodactyly, pectus excavatum or carinatum, high-arched palate, and kyphoscoliosis.
  • Ectopia Lentis: Subluxation of the ocular lens directed DOWNWARD and INWARD (inferonasal). Contrast with Marfan syndrome, where ectopia lentis is UPWARD and OUTWARD (superotemporal).
  • Intellectual Disability & Psychiatric Disturbances: Progressive developmental delay, cognitive decline, and psychiatric symptoms (intellect is completely preserved in Marfan syndrome).
  • Thromboembolism: The hallmark cause of mortality! Severe, premature arterial and venous thromboembolism (deep vein thrombosis, pulmonary embolism, sagittal sinus thrombosis, stroke, and myocardial infarction) occurring in childhood, adolescence, or early adulthood due to endothelial denudation and platelet activation.
• Management: High-dose oral vitamin B6 (pyridoxine) in B6-responsive CBS mutations; dietary methionine restriction supplemented with cysteine (which becomes conditionally essential); oral betaine (trimethylglycine), which provides methyl groups to remethylate homocysteine back to methionine via betaine-homocysteine methyltransferase; folic acid and vitamin B12.

Alkaptonuria

• Enzyme Defect: Autosomal recessive deficiency of homogentisate 1,2-dioxygenase (HGAO) in the tyrosine and phenylalanine degradation pathway.
• Pathophysiology: Homogentisic acid (HGA) accumulates in tissues and is excreted in large amounts in urine. HGA oxidises upon exposure to oxygen and light, polymerising into a dark pigment that binds irreversibly to connective tissue and fibrillar collagen (ochronosis).
• Diagnostic Triad:
  1. Black Urine: Urine freshly voided is normal or amber, but turns brownish-black upon standing, oxidation, or alkalinisation (e.g., addition of NaOH).
  2. Ochronosis: Bluish-black or slate-grey pigmentation of cartilage and connective tissue, most visible in the sclerae (Osler's sign, triangular pigment spots), ear cartilage, and nasal tip.
  3. Ochronotic Arthropathy: Premature, severe degenerative spondyloarthropathy beginning in the 30s. Pigment deposition in intervertebral discs causes disc calcification, disc space narrowing, and lumbar spine ankylosis (resembling ankylosing spondylitis, but sacroiliac joints are spared and HLA-B27 is negative). Large weight-bearing joints (knees, hips, shoulders) develop severe destructive arthritis.
  • Cardiovascular: Ochronotic pigment deposits in cardiac valves, causing severe aortic valve stenosis and coronary artery calcification.
• Management: Symptomatic joint replacement and pain control; nitisinone (inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme immediately upstream of HGA formation, dramatically reducing urinary HGA excretion).