C1Q Deficiency

C1q deficiency is a rare autosomal recessive complement deficiency in which the first component of the classical activation sequence is absent. More than 90% of those affected develop severe, early onset lupus like disease, and many have recurrent bacterial infection.

Pathophysiology. C1q binds immune complexes and apoptotic cell debris and starts classical complement activation. Without it, apoptotic material is not cleared, immune tolerance to nuclear antigens fails, and immune complexes damage skin, kidney and brain. Opsonisation of encapsulated bacteria is also impaired.

Variants in C1QA, C1QB or C1QC cause the deficiency. Onset is in early childhood, and consanguinity is common.

Severe lupus like disease occurs earlier and with higher severity than in other complement deficiencies.

• Photosensitive rash, discoid lesions and mouth ulcers in early childhood
• Glomerulonephritis (lupus nephritis), with haematuria and proteinuria
• Neuropsychiatric lupus: seizures, psychosis
• Arthritis, serositis and cytopenias
• Recurrent bacterial infection: otitis media, pneumonia, meningitis, sepsis
• Gingivitis and recurrent sinopulmonary infection

• Total haemolytic complement (CH50): absent or very low, with normal alternative activation (AH50).
• C1q level: absent or very low by immunoassay, with normal C3 and C4 levels in most.
• Autoantibodies: antinuclear antibody, anti-dsDNA, anti-Ro; titres can be lower than in classical lupus.
• Genetic testing of C1QA, C1QB and C1QC.
• Lupus workup: full blood count, creatinine, urinalysis and urine protein-to-creatinine ratio, renal biopsy for nephritis, direct antiglobulin test.
• Immunoglobulins and specific antibody responses.

Differential diagnosis.

• Systemic lupus erythematosus without complement deficiency
• C1r/C1s, C2 and C4 deficiency
• Acquired C1q deficiency (anti-C1q antibodies, hypocomplementaemic urticarial vasculitis)
• Hereditary angio oedema
• Antibody deficiency
• Cutaneous lupus and juvenile dermatomyositis

• Lupus treatment by organ involvement:
  • Hydroxychloroquine 200 to 400 mg orally daily, not over 5 mg/kg of actual body weight daily (reduce in renal impairment), with eye screening at baseline and yearly after 5 years of use.
  • Prednisolone 0.5 to 1 mg/kg orally daily (maximum 60 mg) for flares, tapered to the lowest dose that controls disease.
  • Mycophenolate mofetil 1 g orally twice daily (children 600 mg/m2 twice daily, maximum 1 g twice daily) or intravenous cyclophosphamide for lupus nephritis, with blood count monitoring.
• Prevention of bacterial infection: phenoxymethylpenicillin 250 mg orally twice daily (children under 6 years 125 mg twice daily; 6 to 11 years 250 mg twice daily) through at least adolescence, and longer after an invasive infection.
• Vaccination: pneumococcal conjugate vaccine, then pneumococcal polysaccharide vaccine at least 8 weeks later, meningococcal ACWY and B vaccines, Haemophilus influenzae type b vaccine, and yearly inactivated influenza vaccine. Avoid live vaccines on immunosuppression.
• Acute fever or illness: this is possible sepsis. After blood cultures, give ceftriaxone 2 g intravenously (children 50 to 80 mg/kg, maximum 2 g) without waiting for results.
• Replacement of C1q: fresh frozen plasma 10 to 15 mL/kg intravenously has been used as a short term source, but C1q has a short half life and sensitisation is possible, so it is not routine.
• Haematopoietic stem cell transplantation can restore C1q from donor monocytes and macrophages and has controlled disease in reported patients; it is considered for severe, refractory disease.

Special groups.

• Pregnancy: lupus flares and antiphospholipid antibodies need joint care by rheumatology and obstetrics.
• Children: weight based dosing, and growth and bone health monitoring on corticosteroids.

Monitoring. Urinalysis, creatinine, full blood count and anti-dsDNA every 3 months. Renal and neurological review at flare. Vaccine titres every 3 to 5 years. Annual eye screening on hydroxychloroquine after 5 years.

Referral and escalation. Refer to paediatric or adult immunology and rheumatology. Urgent for fever, new neurological symptoms, nephritis, or cytopenia.