Signs and symptoms

• Failure to thrive
• Polyuria/polydipsia
  • Can result in chronic volume depletion
• Rickets
• Muscle weakness
• Constipation
  • May be a manifestation of dehydration or electrolyte abnormalities

Lab findings

• Aminoaciduria is the earliest manifestation
  • Progresses to glycosuria, phosphaturia,
• Persistent normal anion gap (nongap) metabolic acidosis (NAGMA)
• Glucosuria
• Hypophosphatemia
• Hypokalemia
• Hyperuricosuria
• Proteinuria
• Low serum 1,25-dihydroxyvitamin D

Cystinosis

• Progresses to full Fanconi syndrome by 12 months of age

Galactosemia

• Classic galactosemia is the most severe form of galactosemia and is caused by complete deficiency of galactose-1-phosphate uridyltransferase (GALT)
• Patients with galactosemia have liver dysfunction, Fanconi syndrome, frequent infections, failure to thrive and cataracts
• Absence of GALT activity in red blood cells is the diagnostic test for galactosemia.

Lowe syndrome

• Inheritance: X-linked recessive
  • OCRL1 on chromosome Xq25-26 encoding the Lowe oculocerebral syndrome 1 (OCRL-1) protein
• Pathogenesis: OCRL-1 is an inositol polyphosphate 5-phosphatase expressed in all cells except hematopoietic cells
  • Phosphoinositides regulate many cellular processes including membrane trafficking and actin cytoskeleton remodeling
  • OCRL-1 has important roles in endosomal trafficking
    • Impaired megalin-cubilin receptor-mediated endocytosis in the proximal tubule leads to LMW proteinuria
      • Normally, LMW proteins bind to megalin on the apical surface of proximal tubular cells and undergo endocytosis, then acidification causes dissociation of the megalin-LMW protein complex and LMW proteins are released to be degraded in lysosomes and megalin is recycled back to the cell surface
      • In Lowe syndrome, megalin recycling is impaired
• Phenotype:
  • Ocular manifestations
    • Bilateral congenital cataracts in nearly all
      • Cataracts develop in utero and can be seen on prenatal ultrasound
    • Infantile glaucoma in ~50%
    • All have impaired visual acuity
  • Neurological manifestations:
    • Central generalized hypotonia
      • Diminished or absent deep tendon reflexes (DTRs)
    • Delayed motor milestones
    • Intellectual disability in almost all, most of which are in the severe-profound range
    • Behavioral abnormalities including aggression, tantrums, repetitive movements, self-injurious behaviors
  • Severe growth impairment
    • Independent of kidney manifestations
  • Musculoskeletal features:
    • Joint hypermobility
    • Scoliosis
    • Osteopenia
    • Up to half of adults get debilitating arthropathy with palmar/plantar fibrosis, subcutaneous nodules, nontender joint swelling, flexion contractures, and bony erosions
  • Kidney manifestations:
    • Proximal tubular dysfunction
      • Low molecular weight (LMW) proteinuria
      • Aminoaciduria
      • Metabolic acidosis
      • Hypophosphatemia
        • Rickets
      • Polyuria
      • Hypercalciuria
        • Can cause nephrocalcinosis and/or nephrolithiasis
    • Over time, may develop tubulointerstitial fibrosis and glomerulosclerosis leading to progressive CKD and progression to ESKD in adulthood

Dent disease

• Inheritance: X-linked recessive
  • CLCN5 in most patients (~60%)
  • OCRL1 in ~20% of patients, termed Dent disease 2 (DD2)
  • ~20% of cases of Dent disease remain genetically unresolved
• Pathogenesis
  • CLCN5 encodes CLC5, a chloride-proton antiporter primarily in the subapical endosomes of the proximal tubule, which is required for maintaining acidification in the endosome
    • Acidification is required for LMW proteins to dissociate from the receptors and undergo degradation
  • Mechanisms of hypercalciuria and hyperphosphaturia are not completely understood, but may be due to high urinary PTH levels
• Phenotypes
  • Dent disease 2 (DD2) due to OCRL1 mutation
    • Depending on where the mutation falls and the type of mutation, OCRL1 mutations also can cause Lowe syndrome, which has extrarenal manifestations [GeneReviews]
    • DD2 is generally considered a milder form of Lowe syndrome without neurologic or ocular manifestations and typically less severe kidney disease
      • They usually do not develop acidosis and they have normal or near normal facial appearance, intelligence, muscle tone, and ocular findings
    • Typically have elevated LDH and CK (CPK)
• Treatment
  • No specific treatments
  • Hypercalciuria can be managed with sodium restriction, thiazide diuretics
  • Hypophosphatemia and rickets may require phosphate, vitamin D supplementation
    • Vitamin D can worsen hypercalciuria
  • Limited data on the use of ACEi
    • ACEi for LMW proteinuria has not been shown to contribute to CKD progression