DISCUSSION
This is the largest series of patients with SLC25A38 associated CSA yet
reported, describing 31 individuals from 24 different families and 11
novel mutations, expanding the total number of reported families and
pathogenic alleles to 92 and 47, respectively.
Despite the diversity of mutations, there are several unexpected aspects
of the SLC25A38 anemia revealed by these studies worth noting. First is
the very limited evidence that there is a genotype-phenotype
correlation. Essentially all patients present at birth or infancy with a
severe hypochromic, microcytic anemia that eventually requires chronic
transfusion. This is in stark contrast with the most common form of
hypochromic microcytic, non-syndromic CSA, XLSA, which is the major
differential diagnosis. Male patients with XLSA may present at birth to
older adulthood. The most severe XLSA cases tend to present at an
earlier age, but it is unusual for a patient to have transfusion
dependent anemia as is typical of SLC25A38 disease. Indeed, the anemia
in XLSA is frequently incidental and may be discovered only by screening
or as a result of investigation of unexplained iron overload. There are,
however, several exceptional cases of patients with SLC25A38 disease
coming to medical attention in their teens or twenties. Three of these
patients had homozygous mutations at codon 134 [p.Arg134His or
p.Arg134Cys] (Fouquet et al., 2019;
Hanina, Bain, Clark, & Layton, 2018;
Le Rouzic et al., 2017). However, two
other patients homozygous for the p.Arg134Cys allele presented at age 2
months and 2 years (W. An et al., 2015;
W. B. An et al., 2019;
Kannengiesser et al., 2011). In our own
cohort, a patient with a homozygous variant at the only incompletely
conserved +5 position of a splice donor site (c.792+5G>C)
presented in his mid-teens. It is certainly possible that other
genotype-phenotype correlations are masked by the clinical imperative to
initiate transfusions in a patient with a HGB less than
~9 g/dL. Indeed, in the publications in which an initial
diagnostic HGB is reported, only one individual, a neonate, had a
hemoglobin >9 g/dL (Guernsey
et al., 2009; Hanina et al., 2018;
Kannengiesser et al., 2011;
Liu et al., 2013;
Wong et al., 2015).
Although clinical practice to transfuse these patients may disguise the
subtle differences between SLC25A38 genotypes, it is abundantly evident
that an SLC25A38 null genotype does not preclude some mitochondrial
glycine being available for heme synthesis. This may be due to other,
less specific transporters, possibly including the highly homologous
protein SLC25A39, or pathways that produce glycine from other amino
acids, such as serine (Amelio, Cutruzzola,
Antonov, Agostini, & Melino, 2014; Kory
et al., 2018). Leveraging these pathways may provide an avenue for
therapy. However, based on limited data, it is unlikely that glycine
supplementation alone will suffice
(Fernandez-Murray et al., 2016;
LeBlanc et al., 2016).
The SLC25A38 anemia is regarded as non-syndromic. Nevertheless, twelve
of the 31 patients described here had developmental or intellectual
disabilities. Similar abnormalities, including psychomotor delay,
hypotonia, facial dysmorphism (Fouquet et
al., 2019), Hypospadias (W. An et al.,
2015), congenital myelomeningocele, patent ductus arteriosus and
ventricular septal defects (Wong et al.,
2015) have been reported in several other patients, but no abnormality
is unusually prevalent across multiple families to suggest a specific
syndromic association.
Three patients who underwent splenectomy developed thrombocytosis and/or
recurrent thrombosis, further supporting the notion that splenectomy may
be contraindicated in SLC25A38 CSA as has generally been advocated in
other patients with microcytic CSAs
(Bottomley & Fleming, 2014;
Fouquet et al., 2019).
The 47 described SLC25A38 pathogenic mutations occur at 40 different
codons. However, nearly one-third (27 of 92) families carry at least one
copy of either the c.324_325del or the c.349C>T allele.
The latter has been identified in families of Acadian
(Guernsey et al., 2009), African American
(current report), South Asian (Ravindra et
al., 2020), Greek (Guernsey et al.,
2009), and Northern European (this report) origin, suggesting that it
has reoccurred on multiple occasions. In fact, in one case (21.1), the
patient is homozygous for the c.349C>T allele, associated
null allele, but one copy also carries a MS variant in a non-conserved
residue in cis (c.[161G>A;349C>T];
p.[Arg54His;Arg117X]). Reanalysis of other SLC25A38 anemia patients
previously reported by us (Guernsey et
al., 2009) identified one other patient having this compound mutant
chromosome (data not shown). Both of these variants occur at
hypermutable cytosine-guanosine (CpG) dinucleotides. This would support
the notion that the p.Arg117X allele has occurred on multiple occasions
and that homozygosity for a disease-associated variant in SLC25A38
should not necessarily be taken as evidence of identity by descent.
Because of the severity and great similarity of the disorder to
transfusion-dependent β-thalassemia (thalassemia major), all of the
patients in our cohort were at one time managed with transfusion and
iron chelation in a manner similar to thalassemia. This is similarly
true of nearly all of the patients described in the literature. Just as
we identified no consistent, distinctive syndromic aspects of the
disease outside the anemia, we did not observe any complications or
undue toxicity as a result of transfusion or iron overload. The oldest
patient in this cohort was 39 years of age, and we are aware of at least
two patients in their early fifties
(Guernsey et al., 2009), suggesting that
modern transfusion and chelation regimens support long-term survival.
Nonetheless, 9 of our patients underwent allogenic HSCT at varying times
during their disease course. Ten other patients
(Guernsey et al., 2009;
Kannengiesser et al., 2011;
Uminski et al., 2020) as well as the
sibling of one patient included in this series
(Kim et al., 2018) are reported to have
been transplanted. Comprehensive details are unavailable for most of
these patients, but when stated, similar to those described here, HSCT
regimens have variously included matched-related and matched unrelated
donors with fully myeloablative or reduced intensity conditioning
regimens. In many cases, aggressive chelation was employed to reduce the
iron burden pre-transplant and phlebotomy was often used post-HSCT to
further normalize iron stores. In all, of 18 patients receiving HSCT, 14
have achieved transfusion independence, 3 grafts failed, and one patient
died in the immediate post-transplant period with follow up ranging from
months to 19 years. In no case has an unusual disease-specific
transplant-related morbidity been reported. Thus, allogeneic HSCT
provides a curative option in SLC25A38 CSA, and may be considered in
young patients with appropriate donors prior to the development of
sequelae of chronic transfusions such as hemosiderosis and
alloimmunization.