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YARS2 congenital sideroblastic anemia
asymptomatic (P8b and P9b) (Table 1B). In a third family (P2a and P2b) (Table 1A), the proband was identified with a severe, new onset anemia at six years of age, and, sub- sequent to her brother’s diagnosis, the younger sibling was found to be anemic. Four of the probands presented within the first two years of life (P5, P6, P7, P9a), and 4 presented in adolescence (P1, P4, P8a, P11). Two patients have died (P1, P5), both from multi-organ failure, one of these following two unsuccessful hematopoietic stem cell transplantations (HSCTs). One patient (P4) has undergone successful HSCT.
The 11 probands all had moderate to severe normocytic to macrocytic anemia. In nine probands, the presence of ringed sideroblasts, ranging from 10% to over 50% of bone marrow erythroblasts, was documented on bone marrow aspiration; marrows were not examined in 3
Table 1B. Clinical data.
Participant ID P7 P8a
other patients and 2 clinically unaffected siblings (Table 1A and B). Eight patients required transfusion; however, one patient spontaneously became transfusion independ- ent at 16 months of age (P7), and 3 patients had periods of hematologic remission (P4, P5, P9a), transiently becoming RBC transfusion independent. In addition to anemia, 3 probands had variable neutropenia and/or thrombocy- topenia (P1, P6, P8a). Four patients were treated with pyri- doxine with no improvement in their anemia (P4, P5, P6, P11).
Two patients had severe lactic acidosis (P1, P3), but the remaining cases in which it was studied had mild or no lactic acidosis (Table 1A and B). Two patients had elevated blood lactate upon light exercise (P4, P8a); those with mild lactic acidosis also tended to have mild myopathy, although one patient with no reported lactic acidosis had
P8b P9a P9b P10 P11
YARS2 variant 1 c.[572G>T;731G>C] c.572G>T c.572G>T c.98C>A c.98C>A c.608G>T c.933C>G (NM_001040436.2) p.(Gly191Val);(Gly244Ala)] p.(Gly191Val) p.(Gly191Val) p.(Ser33*) p.(Ser33*) p.(Ser203Ile) p.(Asp311Glu)
YARS2 variant 2
Year of birth Gender Ethnicity
Consanguinity
Age at presentation
Sideroblastic
anemia
Hemoglobin, g/dL MCV, fL
Abs Retic, M/mL Retic, %
WBC x109/L
ANC x109/L
Platelets x109/L
RS, % of BM erythroblasts Transferrin saturation, % Ferritin, ng/mL
Chelation (Year started)
Lactic acidosis Myopathy Other clinical features
Vital status
c.933C>G
p.(Asp311Glu) 1999 Female Caucasian/ American No
3 months
Severe, transfusion
dependent until 16 months
5.8 94.6 0.037 1.8 8.01 1201 337 47 ND ND No
None Moderate Intermittent diarrhea and abdominal pain
Alive
c.1360_1361insG c.1360_1361insG c.707A>G c.707A>G
p.(Ile454Serfs*10) p.(Ile454Serfs*10) p.(Tyr236Cys) p.(Tyr236Cys)
c.1104-1G>A
p.? 1992 Female Caucasian/ Spanish Unknown 23 years
Moderate
9.6
86 0.088 2.38 7.65 4280 243
32 79.4 (2015) 295 (2015) No
None
None
Asthenia
Alive
c.933C>G
p.(Asp311Glu) 2003 Male Caucasian / Dutch
No
13 years
Severe
transfusion dependent from 13 years
6.6
95
0.018
0.8
4.9
1700
257
81
62 (2016) 180 (2016) Yes (2017)
Mild Mild None
Alive
1963 Female Caucasian/ American No
18 years
Moderate
9.9 111.9 0.059 2.3
6 3600 149
40 66.7 (2015) 387 (2015) No
Exercise induced only Mild Dependent edema, leukopenia, thrombocytopenia, atypical pulmonary carcinoid tumor (age 53)
Alive
1965 Female Caucasian/ American No
49 years (Asymptomatic)
2010
Male Caucasian/ American No
3 months
2010
Male Caucasian/ American No
3 months (Asymptomatic) None
None Severe,
transfused intermittently from 3 months
13.9 2.4 82 113.8 0.106 0.015
2.1 2.4
6.8 10.1 4340 1919 182 537 ND >50 Unknown 45 (2016) Unknown 225 (2016) No No
None None None None None Facial
dysmorphism
Alive Alive
12.8 94.1 0.053 1.3 9.8 3180 414 ND
51 (2015) 42 (2015) No
ND None Facial dysmorphism
Alive
MCV: mean corpuscular volume; retic: reticulocytes; WBC: white blood cell count; ANC: absolute neutrophil count; RS: ringed sideroblasts; BM: bone marrow; ND: not deter- mined.
haematologica | 2018; 103(12)
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