Table 1.

Patients with a mutation in one of the EXOSC genes with TMA.

	Patient 1 [3]	Patient 2 [3]	Patient 3 [2]	Patient 4 [2]	Patient 5 Index (This Report)
Gender	M	M	F	M	F
Age at onset of TMA symptoms	4 months	4.5 months	8 months	7 months	4 months
Gestational age	26 weeks	—	term	term	35 + 2 weeks
Abnormalities since birth	Microcephaly, joint contractures, axial hypotonia	—	Pontocerebellar hypoplasia	Pontocerebellar hypoplasia	Cerebellar hypoplasia, symmetrical fetal growth restriction
Presenting symptoms	Fever, mild respiratory symptoms	Pyrexia, diarrhea, reduced drinking	Bronchiolitis in need of mechanical ventilation	Lower respiratory tract infection in need of mechanical ventilation	Fever, illness
(Potential) trigger	SARS-CoV-2 infection	SARS-CoV-2 infection	RSV infection	Unspecified respiratory virus	Rotavirus infection
Timing of TMA symptoms	5 days after onset of COVID-19	5 days after onset of COVID-19	At presentation	At presentation	6 days after presentation with fever
Complement analysis
CFH	Normal	Normal	Slightly elevated	Normal	ND
CFI	Normal	Normal	Slightly decreased	Normal	ND
CFB	Normal	Normal	ND	ND	ND
CFD	Normal	Normal	ND	ND	ND
Complement activity (CH50)	Normal	Normal	—	—	Normal
Anti-CFH autoantibodies	No antibodies	No antibodies	No antibodies	No antibodies	No antibodies
sC5b-9	456 ng/mL Slightly above normal range	311 ng/mL Slightly above normal range	ND	ND	ND
Antibodies against LPS O26, O55, O103, O157	—	—	—	—	No antibodies
Fecal diagnostics: STEC PCR	Negative	Negative	Negative	Negative	Negative
Genetic analysis for TMA	No pathogenic mutation in ADAMTS13, C3, CD46, CFB, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, DGKƐ, MMACHC, THBD	No pathogenic mutation in ADAMTS13, C3, CD46, CFB, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, DGKƐ, MMACHC, THBD	No pathogenic mutation in CFH, CFI, CD46, C3, CFB, DGKƐ, THBD, MTR, VTN, MMACHC	No pathogenic mutation in CFH, CFI, CD46, C3, CFB, DGKƐ, THBD, MTR, VTN, MMACHC	No pathogenic mutation in CFH (including MLPA), CFI, CD46, C3, CFB, DGKƐ
Gene associated with PCH	EXOSC3	EXOSC3	EXOSC3	EXOSC3	EXOSC5
Nucleotide alterations	c.92G>C	c.92G>C	c.395A>C, c.341_343del	c.395A>C, c.92G>C	c.230_232del
Consequence at protein level	p.(Gly31Ala)	p.(Gly31Ala)	p.(Asp132Ala), (p.Glu114_Pro115delinsAla)	p.(Asp132Ala), p.(Gly31Ala)	p.(Glu77del)
Zygosity	Homozygous	Homozygous	Compound heterozygous	Compound heterozygous	Homozygous
Eculizumab treatment	Yes, 300 mg 0, 8, and 28 days after onset of TMA	Yes, 300 mg 0, 7, and 26 days after onset of TMA	Yes, single dose	Yes, continuous eculizumab for months	Yes, single dose, 300 mg
Response to eculizumab	Unresponsive	Unresponsive	No response	Initial improvement, TMA recurrence under eculizumab treatment after 4 months	Creatinine levels, hemoglobin levels, thrombocytes, and LDH were normalized within 2 weeks, likely due to conservative treatment rather than to eculizumab therapy
Outcome	Slight decrease in kidney function, persisting hypertension, persisting proteinuria.	Persisting hypertension, mild persisting proteinuria, normal kidney function.	Due to the underlying severity of the neurological disorder, palliative care was initiated.	Initially improvement was seen, relapse of TMA 4 months later with ongoing eculizumab treatment, patient died shortly thereafter.	Improvement of kidney function. Patient died at age 6 months after palliative care was initiated due to severity of the neurological disorder.

Abbreviations: ADAMTS13, a disintegrin and metalloprotease with thrombospondin motifs; AKI indicates acute kidney injury; Membrane cofactor protein, CD46; CFB, complement factor B; CFH, complement factor H; CFHR, complement factor H related; CFI, complement factor I; DGKƐ, Diacylglycerol kinase ɛ; MMACHC, methylmalonic aciduria and homocystinuria type C protein; MTR, 5-methyltetrahydrofolate-homocysteine methyltransferase; ND, not determined; PCH, pontocerebellar hypoplasia; THBD, thrombomodulin; TMA, thrombotic microangiopathy; VTN, vitronectin; —, not available in previously reported cases. For EXOSC5, transcript NM_020158.4 was used.