Prophylactic immunoglobulin therapy for pediatric congenital myotonic dystrophy

Abstract Congenital Myotonic Dystrophy (CMD) is an autosomal dominant hereditary disease caused by mutations in the dystrophia myotonica protein kinase gene. Patients with CMD often exhibit low immunoglobulin (Ig) G levels. While Ig replacement therapy for low IgG levels has been reported in several adult cases, there have been no reports on pediatric patients. This study presents a first pediatric case where Ig replacement therapy effectively eliminated susceptibility to infections. The CMD patient, a 1-year-old Japanese female with a history of premature birth and necrotizing enterocolitis, developed recurrent severe bacterial infections due to hypogammaglobulinemia. Intravenous immunoglobulin (IVIG) (600 mg/kg/month) was administered but failed to maintain sufficient serum trough IgG levels. The dosage was increased to 2 g/kg/month, and later, the treatment shifted to subcutaneous immunoglobulin (SCIG), resulting in a stable serum trough IgG level above 700 mg/dL for one year. The cause of hypogammaglobulinemia in CMD patients remains unclear, but potential mechanisms, including IgG-mediated hypercatabolism by alterations in the neonatal Fc receptor, have been considered. Genetic testing ruled out common variable immunodeficiency, and other potential causes were excluded. The study suggests that higher doses of IVIG or SCIG can effectively prevent severe infections associated with CMD-induced hypogammaglobulinemia in children. IMPACT STATEMENT This case report sheds light on the efficacy of immunoglobulin therapy in pediatric congenital myotonic dystrophy (CMD). We anticipate that our findings will have a positive impact on clinical practice by providing insights into the prevention of severe infections associated with CMD-induced hypogammaglobulinemia. This research is of great interest to the readers of the journal as it addresses an unmet need in pediatric CMD management by providing a strategy for successful immunoglobulin therapy for the treatment of pediatric CMD.

To the Editor, Congenital myotonic dystrophy (CMD) is an autosomal dominant hereditary disease caused by mutations in the dystrophia myotonica protein kinase gene (DMPK) located on the long arm of chromosome 19 (13.2-13.3)[1].The primary clinical manifestations of CMD include muscle contractions and weakness.While CMDs are not currently classified as inborn errors of immunity according to the report by the International Union of Immunological Societies (2022 Update) [2], various complications, such as hypogammaglobulinemia, can occur during the course of the disease.Prophylactic administration of intravenous immunoglobulin (IVIG) has been used to prevent hypogammaglobulinemia development in adult patients with CMD; however, such interventions in pediatric patients have not been reported.Here, we present the first case of pediatric CMD where both IVIG and subcutaneous immunoglobulin (SCIG) were administered to prevent severe bacterial infections (SBIs) caused by CMD-related hypogammaglobulinemia.
A 1-year-old Japanese female was admitted to our hospital due to fever.Her medical history revealed that she was delivered by emergency cesarean section at 32 weeks and 2 days of gestation, with a birth weight of 1491 g.At 1 month old, she developed necrotizing enterocolitis and an intestinal stoma.Due to short bowel syndrome-induced malnutrition, she received total parenteral nutrition.At that time, following an investigation for hyperCKemia, the patient's mother was diagnosed with CMD.Southern blot analysis confirmed the patient's CMD diagnosis, revealing large cytosine-thymine-guanine (CTG) repeat expansion (> 2000 repeats) in the DMPK gene (Figure 1).At 2 months old, the patient's Hypogammaglobulinemia; pediatric congenital myotonic dystrophy; intravenous immunoglobulins; subcutaneous immunoglobulins; neonatal fc receptor immunoglobulin (Ig) G level was low (148 mg/dL, normal range: 176-601 mg/dL).She experienced a recurrent abdominal abscess and a catheter-induced bloodstream infection at 2 and 3 months old, respectively.Therefore, IVIG was administered at 400 mg/ kg/month (Figure 2).At 1 year of age, she was referred to our department for the treatment of recurrent SBIs, which included catheter-induced bloodstream infection, urinary tract infection, and bacteremia.She received parenteral antibiotics.At that time, her height and weight were 62.0 cm (-4.1 standard deviations; SDs) and 5.1 kg (-3.8 SDs), respectively.Her white blood cell count was 8,030/ μL, containing 26.1% neutrophils and 61.5% lymphocytes.Her levels of serum total protein and albumin were below normal at 5.3 g/dL (normal range: 6.1-7.9 g/dL) and 3.2 g/dL (normal range: 3.4-4.2g/ dL), respectively.The concentrations of serum Igs were 376 mg/dL IgG (normal range: 345-1236 mg/ dL), 47 mg/dL IgA (normal range: 11-106 mg/dL), and 25 mg/dL IgM (normal range: 41-173 mg/dL).Flow cytometry results of lymphocyte subpopulations revealed that her cell counts were within the normal range at 3007 cells/μL CD3+ (normal range: 2542-4933 cells/μL), 2252 cells/μL CD4+ (normal range: 1573-2949 cells/μL), 805 cells/μL CD8+ (normal range: 656-1432 cells/μL), 1412 cells/μL CD19+ (normal range: 733-1338 cells/μL), and 435 cells/μL CD16+/CD56+ (normal range: 186-724 cells/μL).In addition, lymphocyte proliferation tests showed normal responses to phytohemagglutinin and concanavalin A. The urine test revealed the absence of proteinuria.At 1 year of age, the patient received IVIG (600 mg/kg/month), and her nutritional status improved through adjustments in parenteral and enteral nutrition.However, her serum IgG concentration dropped below 500 mg/dL, resulting in recurrent SBIs.Starting from 1 year and 11 months of age, the patient received IVIG (2 g/kg/ month) to maintain a trough serum IgG concentration above 500 mg/dL.At 2 years and 11 months of age, treatment was changed to SCIG (400 mg/kg/ week), and a trough IgG level above 700 mg/dL was maintained for six months.Ultimately, the patient and her parents provided positive feedback on the treatment, expressing a significant improvement in the patient's quality of life.The parents emphasized the elimination of hospitalization requirements, weight gain as a positive outcome, and an improved capacity to participate in daily activities.
The exact cause of hypogammaglobulinemia in patients with CMD remains unclear.Hypogammaglobulinemia is characterized by decreased levels of immunoglobulins resulting from antibody production, inborn errors of immunity, and various other diseases [3].In patients with CMD, the number of bone marrow cells and peripheral blood lymphocytes, as well as the number and ratios of CD3+, CD4+, CD8+, and CD19+ lymphocytes, remain within the normal range [4,5].Furthermore, in vitro lymphocyte proliferation tests and in vitro IgG production tests show normal results [4].In patients with CMD, hypogammaglobulinemia might be attributed to IgG-mediated hypercatabolism by alterations in the neonatal Fc receptor (FcRn) [6].FcRn plays a role in prolonging the circulating half-life of IgG molecules and regulating their metabolism.Recently, FcRn antagonists were found to shorten the circulating half-life of IgG molecules and reduce their concentration in the blood [3].From a genetic perspective, in Japanese patients with CMD, the serum IgG concentration is inversely correlated with the number of CTG repeats, with a greater reduction observed as the repeat count increases [5].
To investigate the underlying cause of hypogammaglobulinemia in this case, a genetic test for common variable immunodeficiency was performed.No previously reported pathogenic variants were detected, and lymphocyte count and proliferation fell within the normal range.Initially, premature birth, malnutrition, a protein-losing enteropathy, and transient hypogammaglobulinemia (THI) were considered as possible causes of the hypogammaglobulinemia.However, even after one year of life and an improvement in the nutritional status of the patient, as evidenced by the resolution of hypoalbuminemia and hypoproteinemia, the patient's hypogammaglobulinemia persisted.The alpha-1-antitrypsin levels in feces measured during the clinical course consistently remained in the normal range.Flow cytometry results of lymphocyte subpopulations revealed that, at 3 years of age, both the absolute counts and the ratio of memory B cells to naive B cells were within the normal range.Patients with THI, whose IgG molecule half-life and metabolism regulation do not necessitate massive IgG replacement treatment within a short period of time, as is evident in this patient.Furthermore, in this patient, the CTG repeat count was found to be above 2000, indicating a significant expansion.Consequently, as all other possible causes were excluded, it was determined that CMD was the cause of hypogammaglobulinemia in this patient.
Currently, there are no guidelines for IgG therapy to manage CMD-induced hypogammaglobulinemia.A previous study reported the use of immunoglobulin replacement therapy in two adult patients with CMD-related hypogammaglobulinemia, who were from the same family [7].IVIG was initially administered at a dose of 400 mg/kg/month.In one family member, trough IgG concentration was increased and SBI symptoms were reversed with monthly IVIG, while the other family member required bimonthly administration of IVIG to increase IgG concentration to a normal level.In our study, IVIG was initially administered at a dose of 600 mg/kg/month to address low serum IgG levels.However, this failed to maintain a trough IgG concentration sufficient to prevent infections.By increasing the dose to 2 g/kg/month, the serum trough IgG levels were successfully maintained at 500 mg/dL or higher, thereby eliminating susceptibility to infections and improving the patient' s quality of life.One year after switching to weekly SCIG infusions, the patient' s serum IgG levels stabilized, and no severe infections occurred.The rapid reduction in serum IgG concentrations in the short-term following administration of exogenous gamma globulin might be attributed to an increase in FcRn-mediated IgG degradation.To limit the burden on patients in cases where IgG metabolism is accelerated and the target serum IgG level needs to be maintained, it is necessary to administer the maximum IgG dose or perform SCIG infusions with shorter administration intervals.This case suggests that the administration of IVIG at a monthly dose of 2 g/kg, or SCIG at a weekly dose of 400 mg/kg, can effectively prevent severe infections associated with CMD-induced hypogammaglobulinemia in children.Further case data are required to provide further insights into the clinical aspects of CMD-induced hypogammaglobulinemia.

Figure 1 .
Figure 1.Southern blot analysis of EcoRI-(lane e), BglI-(lane g), and PstI-(lane Ps) digested genomic dna from the 1-year-old Japanese female with congenital myotonic dystrophy.Black arrows indicate the normal allele and red arrows indicate the cytosine-thymine-guanine repeat expansion allele of the dystrophia myotonica protein kinase gene (DMPK) of the patient, respectively.

Figure 2 .
Figure 2. diagram illustrating the clinical course of the patient throughout treatment.The presence of severe bacterial infections (SBIs) are indicated in black above the figure.administration time and doses of intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (ScIg) are indicated by arrows and a grey bar, respectively, with the thickness of each arrow corresponding to the dose.changes in the immunoglobulin (Igg) concentration, c-reactive protein (cRP) concentration, height and weight of the patient with time are also indicated.