Abstract
Glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the conversion of glutamic acid into γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (CNS). GAD is widely expressed in the CNS and pancreatic β-cells. GABA produced by GAD plays a role in regulating insulin secretion in pancreatic islets. Anti-GAD antibody is an established marker of type 1 diabetes mellitus (T1DM) and is also associated with stiff-person syndrome (SPS) and several other neurological disorders, including ataxia, cognitive impairment, limbic encephalitis, and epilepsy, collectively referred to as GAD antibody-spectrum disorders (GAD-SD). We report the case of a 17-year-old male patient who developed GAD-SD and T1DM after allogeneic hematopoietic cell transplantation (HCT). He presented with memory disorders, including feelings of déjà vu, accompanied by vomiting and headaches, and exhibited abnormal brain magnetic resonance imaging and electroencephalogram results. In addition to elevated fasting plasma glucose and glycated hemoglobin levels, markedly elevated anti-GAD antibody levels were detected in the serum and cerebrospinal fluid. Based on these findings, the patient was diagnosed with GAD-SD and T1DM and treated with methylprednisolone, followed by multiple daily insulin injections. We also reviewed previously reported cases of GAD-SD following HCT and multiple positive islet-related antibodies.
Introduction
Glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the conversion of glutamic acid into γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (CNS) [1]. GAD is widely expressed in the CNS and pancreatic β-cells, where GABA produced by GAD plays a role in the regulation of insulin secretion [2]. Anti-GAD65 antibody was first described in patients with type 1 diabetes mellitus (T1DM) and has since been established as a disease marker. Approximately 80% of patients with T1DM are positive for serum anti-GAD antibodies [3]. Furthermore, this antibody is also found in the serum and cerebrospinal fluid (CSF) of patients with stiff-person syndrome (SPS), which is characterized by progressive disabling muscle rigidity, hyperreflexia, and spasms [4]. In addition to SPS, anti-GAD antibodies are associated with several neurological disorders including cerebellar ataxia, cognitive impairment, limbic encephalitis, seizures, and autoimmune epilepsy. These disorders are collectively referred to as GAD antibody-spectrum disorders (GAD-SD) [5]. Notably, approximately 30–60% of patients with GAD-SD have comorbid T1DM [6, 7].
Hematopoietic cell transplantation (HCT) is a crucial treatment modality for many hematological malignancies in children, such as acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, and severe aplastic anemia [8, 9]. Neurological complications following HCT include central nervous system infections, cerebrovascular disorders, neurotoxicity, and cognitive impairments [10]. However, autoimmune neurological disorders are rarely observed.
We report the case of a male patient with a history of allogeneic HCT for severe aplastic anemia who subsequently developed GAD-SD and T1DM.
Case Report
The patient was a 17-year-old Japanese male, height of 156.7 cm (–2.4 SD) and weight of 53.9 kg (BMI 22.0), with no obvious physical abnormalities. He was diagnosed with severe aplastic anemia at age 14 and underwent allogeneic HCT (bone marrow transplantation) from an HLA-matched unrelated female donor, following conditioning with total body irradiation (3 Gy), anti-human thymocyte immunoglobulin, and cyclosporine. One year after transplantation, immunosuppressive therapy was discontinued, and complete remission was maintained for nearly three years, with no abnormalities observed, including endocrine evaluations. T-cell and B-cell populations remained stable after transplantation, with approximately 70% and 15% of T and B cells, respectively. By the age of 16 years, development of the external genitalia was consistent with normal male levels (testicular volume >20 mL, and pubic hair development at Tanner stage 4). Endocrine evaluation revealed LH at 8.58 IU/L, FSH at 11.63 IU/L, testosterone at 530 ng/dL, IGF-I at 334 ng/mL, TSH at 1.46 μIU/mL, free T4 at 1.43 ng/dL, glycated hemoglobin (HbA1c) at 5.1%, and random blood glucose level of 101 mg/dL.
At 17, he experienced memory disturbances characterized by feelings of déjà vu, accompanied by episodes of vomiting and headaches. No other neurological symptoms, such as muscle stiffness, spasms, or rigidity were observed. No signs of fever or neck stiffness were observed. The patient’s random blood glucose level was 157 mg/dL, and the HbA1c was 5.3%. Brain magnetic resonance imaging (MRI) revealed right amygdala enlargement (Fig. 1), and electroencephalogram (EEG) showed slow-wave discharges in the right temporal region. Therefore, the patient was diagnosed with temporal lobe epilepsy and treated with lacosamide and levetiracetam. However, six months after the diagnosis, the neurological symptoms did not improve, leading to further investigations, including for encephalitis. Serum laboratory data revealed an elevated fasting plasma glucose (FPG) level of 310 mg/dL and an HbA1c level of 9.1%. Serum C-peptide and urine C-peptide levels were 2.68 ng/mL and 32.3 μg/day, respectively. The serum levels of islet cell antibodies were assessed, revealing markedly elevated levels of anti-GAD antibody at 2,279,590 U/mL, anti-IA-2 antibody at >30 U/mL, and anti-zinc transporter 8 (ZnT8) antibody at >2,000 U/mL. Insulin autoantibody (IAA) was within the normal range (14.9 U/mL). Anti-GAD antibodies specifically recognizing GAD65 were measured using a Cosmic kit and quantified by diluting the serum with normal saline. Other autoimmune antibodies, such as antinuclear antibody, anti-DNA antibody, anti-SS-A/Ro antibody, anti-SS-B/La antibody, and anti-TPO antibody, were found to be negative, except for the anti-thyroglobulin antibody. Serum TSH and free T4 levels were within the normal range. Subsequently, lumbar puncture was performed, and CSF analysis showed a normal cell count, but slightly elevated protein and glucose levels. Additionally, anti-GAD antibody level (>2,000 U/mL), anti-IA-2 antibody (9.5 U/mL), and anti-ZnT8 antibody (127 U/mL) levels in the CSF were elevated. There was no evidence of bacterial or viral infection in blood or CSF samples. The serum and CSF laboratory results are summarized in Table 1.
Fig. 1
Brain magnetic resonance imaging. Axial and coronal FLAIR images show hyperintensity in the right tonsil with enlargement (yellow circles).
Table 1 Laboratory Data of the Patient
| Parameter |
Unit |
Measurement |
Reference range |
| WBC |
(×102/μL) |
52.9 |
39–98 |
| RBC |
(×104/μL) |
462 |
427–570 |
| Hb |
(g/dL) |
15.4 |
13.5–17.6 |
| Plt |
(×104/μL) |
22.2 |
13.1–36.2 |
| AST |
U/L |
20 |
13–30 |
| ALT |
U/L |
36 |
10–42 |
| γ-GT |
U/L |
23 |
<70 |
| CK |
U/L |
33 |
32–180 |
| Na |
mEq/L |
135 |
138–145 |
| K |
mEq/L |
4.3 |
3.6–4.9 |
| Cl |
mEq/L |
101 |
99–109 |
| BUN |
mg/dL |
14.1 |
8.0–22.0 |
| Cre |
mg/dL |
0.7 |
0.61–1.04 |
| TP |
g/dL |
7.2 |
6.7–8.3 |
| CRP |
mg/dL |
0.09 |
0.00–0.30 |
| Fasting plasma glucose |
mg/dL |
310 |
69–104 |
| HbA1c |
% |
9.1 |
4.6–6.2 |
| C-peptide |
ng/mL |
2.68 |
0.61–2.09 |
| Urine C-peptide |
μg/day |
32.3 |
22.8–155.2 |
| TSH |
μIU/mL |
1.6 |
0.61–4.23 |
| FT4 |
ng/dL |
1.66 |
0.75–1.45 |
| IgG |
mg/dL |
954 |
870–1700 |
| IgM |
mg/dL |
57 |
33–190 |
| Anti -GAD antibody |
U/mL |
2,279,590 |
<5.0 |
| Anti-IA-2 antibody |
U/mL |
>30 |
<0.6 |
| Anti-ZnT8 antibody |
U/mL |
>2,000 |
<15.0 |
| IAA |
nU/mL |
14.9 |
<125 |
| Anti-Tg antibody |
IU/mL |
64.8 |
<19.3 |
| Anti-TPO antibody |
IU/mL |
<9 |
<3.3 |
| C3 |
mg/dL |
133 |
86–160 |
| C4 |
mg/dL |
25.3 |
17–45 |
| RF |
IU/mL |
<3 |
0–15 |
| Antinuclear antibody |
titer |
40 |
0–40 |
| Anti-DNA antibody |
IU/mL |
<1.7 |
0.0–6.0 |
| Anti-SS-A/Ro antibody |
U/mL |
<1.0 |
0.0–10.0 |
| Anti-SS-B/La antibody |
U/mL |
<1.0 |
0.0–10.0 |
| <CSF analysis> |
|
|
|
| Cells |
(μL) |
5 |
0–5 |
| Protein |
(μL) |
54 |
10–40 |
| Glucose |
(mg/dL) |
107 |
50–75 |
| Anti-GAD antibody |
U/mL |
>2,000 |
|
| Anti-IA-2 antibody |
U/mL |
9.5 |
NA |
| Anti-ZnT8 antibody |
U/mL |
127 |
NA |
Based on these findings, the patient was diagnosed with GAD-SD in conjunction with T1DM. Intravenous methylprednisolone pulse therapy (500 mg/day for six days) was administered to treat the neurological symptoms. Blood glucose levels temporarily increased to >500 mg/dL during treatment. Although neurological symptoms improved after therapy, hyperglycemia persisted (FPG, 309 mg/dL). Consequently, multiple daily insulin injections (MDI) therapy was initiated using insulin aspart and insulin degludec. After six months of MDI, the serum thyroglobulin antibody level was negative, however, the serum anti-GAD antibody level remained elevated (1,340,000 U/mL). The patient’s serum C-peptide level was 4.21 ng/mL, with a random blood glucose level of 261 mg/dL. An HbA1c level of 7.0% was achieved with a daily dose of 15 units of insulin aspart and 7 units of insulin degludec. After 12 months of MDI, the patient exhibited a well-controlled HbA1c level of 6.0%, with a daily dosage of 24–30 units of insulin aspart and 7 units of insulin degludec. The serum C-peptide level was 2.06 ng/mL, and a random blood glucose level was 149 mg/dL. However, serum levels of anti-GAD antibody (746,000 U/mL), anti-IA-2 antibody (>30 U/mL), and anti-ZnT8 antibody (>2,000 U/mL) remained elevated. While no neurological symptoms were observed, EEG continued to show slow-wave discharges in the right temporal region. Therefore, lamotrigine was added to the treatment regimen. The continuous glucose monitoring (CGM) data from this period are shown in Fig. 2. There was no family history of T1DM, but the patient’s maternal grandfather had type 2 diabetes mellitus.
Fig. 2
Continuous glucose monitoring profile using the Dexcom G6 device. Insulin management involved injecting 8–10 units of insulin aspart before each meal and 7 units of insulin degludec once daily. TAR: Time Above Range; TIR: Time In Range; TBR: Time Below Range.
A Graphical Abstract presents the timeline of GAD-SD development three years after HCT and the corresponding changes in HbA1c, anti-GAD antibody, anti-IA-2 antibody, and anti-ZnT8 antibody levels, and treatment interventions over the course of approximately one year.
Graphical Abstract
Discussion
Here we report a case of GAD-SD and T1DM in a male patient who underwent allogeneic HCT. To our knowledge, this is the second reported case of GAD-SD with T1DM following HCT. This patient presented with memory disorders, vomiting, and headaches. Brain MRI revealed enlargement of the right amygdala, and the EEG detected slow-wave discharges in the right temporal region. Additionally, high levels of anti-GAD antibodies were identified in both serum and CSF. These findings are consistent with those of previously reported cases of GAD-SD [11, 12]. The clinical spectrum of GAD-SD has expanded to overlap with that of other neurocognitive disorders, including SPS, cerebellar ataxia, limbic encephalitis, epilepsy, and myoclonus. Cognitive impairments, such as forgetfulness, memory impairment, and dementia are also frequently observed [12-14].
Notably, the serum anti-GAD antibody level in this patient was exceedingly high (>2,270,000 U/mL). As previously reported, individuals with SPS typically exhibit significantly higher serum anti-GAD antibody titers than those with T1DM without neurological symptoms, where the titers are generally <1,000 U/mL. However, this patient’s antibody titer was the highest among cases of GAD-SD reported in the literature [15-17]. Excessively high anti-GAD antibody levels in this patient may be attributed to several factors related to post-bone marrow transplantation immune mechanisms. New T and B cells produced by allogeneic bone marrow might lack proper regulation and memory, leading to an overreaction to the patient’s tissues, perceived as non-self [18, 19]. Additionally, graft-versus-host disease may involve donor-derived T cells attacking the recipient’s tissues, causing chronic inflammation and heightened immune sensitivity [18, 19]. Moreover, abnormal immune reconstruction following transplantation can result in autoimmune-like conditions, where T cells overreact to self-antigens [18, 19]. Collectively, these mechanisms may result in excessive B cell activation and antibody production.
In addition to anti-GAD antibodies, elevated CSF levels of anti-IA-2 and anti-ZnT8 antibodies were detected in the case. Although the elevation of anti-GAD antibodies in the CSF with intrathecal production has been well documented [11], no published reports exist on the measurement of anti-IA-2 or anti-ZnT8 antibodies in the CSF of patients with GAD-SD. The lower levels of these antibodies in the CSF than the blood may indicate a partial disruption of the blood-brain barrier, possibly due to encephalitis or previous treatments, such as bone marrow transplantation, allowing some antibodies to enter the CSF. However, the potential impact of these antibodies on the CNS remains unclear.
The patient maintained good glucose control with a low daily insulin dose, as demonstrated by CGM. Despite persistently high levels of anti-GAD, anti-IA-2, and anti-ZnT8 antibodies for over a year after the onset of GAD-SD, serum C-peptide levels remained stable. These findings suggested that β-cell function was preserved, allowing continued insulin secretion in this patient. A previous study showed that anti-GAD antibody titers are positively associated with the C-peptide index in patients with acute-onset T1DM, indicating that higher titers may be correlated with slower disease progression [20]. Latent autoimmune diabetes has also been reported in patients with SPS who test positive for anti-GAD antibodies [21]. In addition, while about 80% of patients with T1DM and without neurological symptoms are anti-GAD positive [3], only 30–60% of patients with SPS and high anti-GAD levels develop T1DM [6, 7]. Studies have demonstrated that anti-GAD antibodies, particularly those targeting GAD65, exhibit distinct recognition patterns in T1DM and SPS. In T1DM, anti-GAD antibodies primarily target conformational epitopes located in the middle and C-terminus of GAD65 molecules. In contrast, in SPS, these antibodies recognize both linear and conformational epitopes at the N-terminus and C-terminus of GAD65 molecules [22, 23]. Thus, the effect of anti-GAD antibodies on β-cell function in GAD-SD might differ from that in T1DM. In T1DM, β-cell destruction is mainly T-cell-mediated, whereas in GAD-SD, the mechanism might differ, resulting in milder or slower β-cell dysfunction. However, the effects of other islet autoantibodies on β-cell function in this patient remain unclear and longitudinal investigations are required.
The patient developed GAD-SD and T1DM three years after undergoing allogeneic HCT. To date, six patients, including this patient, have been reported to develop GAD-SD following HCT (Table 2) [14, 24-27]. The onset of GAD-SD after HCT ranged from 10 months to 4 years, and various neurological symptoms were observed. Among these, only two patients (the present case and case 4) developed T1DM. Case 4 underwent HCT for pineoblastoma and subsequently developed hypoinsulinemia and hyperglycemia, with markedly elevated anti-GAD antibody levels. However, details regarding diabetes treatment in this case were not documented [26]. Neurological autoimmune disorders following HCT are rare and their precise mechanisms, including potential genetic susceptibility, infections, prior chemotherapy, and donor cell characteristics, are still not well understood [28]. The clinical aspects of β-cell function, treatment responsiveness, and outcomes in such cases are largely unknown.
Table 2 Previously reported anti-GAD antibody spectrum disorders in patients who underwent hematologic cell transplantation
| Case |
Sex |
Malignancy |
Age at malignancy onset (y) |
Treatment for malignancy |
GAD-SD onset post-HCT |
Symptoms of GAD-SD |
anti-GAD antibody |
Diabetes-related Data |
Treatments for GAD-SD |
Clinical outcomes |
Reference |
| Serum (U/mL) |
CSF (U/L) |
| 1 |
M |
Severe aplastic anemia |
14 |
Allogenic HCT (BMT) |
3 years |
Memory disorders, vomiting, headaches |
2,279,590 |
>2,000 |
FPG 301 mg/dL, HbA1c 9.1%, C-peptide 2.68 ng/mL |
Methylprednisolone |
Clinical improvement, persistent EEG abnormalities |
This case |
| 2 |
F |
Multiple myeloma |
31 |
Autologous HCT (BMT) |
2 years |
Myoclonic jerks, wide-based slow and stiff gait |
104 (nmol/L)a |
— |
NA |
IVIG, Methylprednisolone |
Truncal stiffness and gait impairment persist |
[24] |
| 3 |
F |
Acute myeloid leukemia most probably secondary to CMML |
62 |
Allogenic HCT from sibling |
20 months |
Diplopia, slurred speech, gait disturbance |
8.7 b |
2.65 b |
NA |
Methylprednisolone, IVIG, rituximab |
Died 4 months later |
[25] |
| 4 |
F |
Pineoblastoma |
5 |
HCT |
13 months |
Seizure clustering, altered mental status |
65,100 |
— |
Hypoinsulinemia and hyperglycemia |
Methylprednisolone, IVIG |
Mental status gradually and partially recovered |
[26] |
|
|
|
|
|
27 months |
Status epilepticus, altered mental status |
142,000 |
238 |
Methylprednisolone, IVIG, plasma exchange, tacrolimus |
Unable to communicate or walk independently, require total assistance |
|
| 5 |
M |
B-cell chronic lymphocytic leukemia |
50 |
Allogenic HCT (PBSC) |
4 years |
Brachial dystonic seizures, mild cognitive impairments in perceptual-motor skills, learning, and memory |
1:1,600 c |
— |
NA |
Methylprednisolone, immunoadsorption therapy, rituximab |
Reduction of motor and cognitive impairments |
[14] |
| 6 |
M |
Acute promyelocytic leukemia |
28 |
Autologous HCT |
10 months |
Mental status disturbance, seizures |
>2,000 |
>2,000 |
NA |
Methylprednisolone, IVIG |
Improvement |
[27] |
|
|
|
|
|
2 years |
Diplopia, left peripheral facial palsy |
>2,000 |
>2,000 |
NA |
IVIG, plasma pheresis |
Improvement |
|
|
|
|
|
|
4 years |
Spastic paraparesis, thermo-algic hypoesthesia |
— |
— |
NA |
Azathioprine, rituximab |
Clinically stable with negative anti-GAD antibodies |
|
GAD-SD, GAD antibody-spectrum disorders; CSF, cerebrospinal fluid; HCT, hematopoietic cell transplantation; BMT, bone marrow transplantation; IVIG, intravenous immune globulin; CMML, chronic myelomonocytic leukemia; PBSC, peripheral blood stem cell; FPG, fasting plasma glucose; NA, not applicable.
a Reference range: <0.02 nmol/L.
b Anti-GAD antibodies were measured by RIA. Reference range: <1.0 U/mL in serum, <1.0 U/mL in CSF.
c Measured by indirect immunohistochemistry (GAD-IgG) using serial dilutions of the patient sample.
To the best of our knowledge, this is the first reported case of GAD-SD in which three islet autoantibodies, anti-GAD, anti-IA-2, and anti-ZnT8, were detected. This case provides new insights into islet autoantibody profiles in patients with GAD-SD. In previous studies, 11 patients with GAD-SD were reported to be positive for anti-IA-2 antibodies and/or IAA across five studies (Table 3) [7, 29-33]. Among these 11 patients, three developed IDDM after the onset of GAD-SD, while one had prior IDDM. Two patients did not develop IDDM, and the status of the remaining five patients remains unclear, leaving questions about their disease progression. In our case, the patient’s HbA1c level increased when neurological symptoms appeared, suggesting that glucose intolerance may have started at approximately the same time as the onset of GAD-SD. Further studies are required to explore the relationship between the number of autoantibodies and development of IDDM in patients with GAD-SD, particularly with the progression of glucose intolerance and disease severity.
Table 3 Previously reported GAD-SD patients with multiple positive islet-related autoantibodies
| Age |
Sex (y) |
Onset of IDDM |
anti-GAD antibody |
anti-IA-2 antibody |
IAA |
ZnT8 antibody |
Reference |
| 17 |
M |
Possibly concurrent with GAD-SD |
+ |
+ |
– |
+ |
This case |
| 54 |
M |
Preceded by GAD-SD |
+ |
+a |
+ |
NA |
[29] |
| NA |
NA |
Followed by GAD-SD |
+ |
+ |
+ |
NA |
[30] |
| NA |
NA |
Followed by GAD-SD |
+ |
+ |
+ |
NA |
|
| NA |
NA |
Followed by GAD-SD |
+ |
+ |
+ |
NA |
|
| NA |
NA |
NA |
+ |
+ |
NA |
NA |
[31] |
| NA |
NA |
NA |
+ |
+ |
NA |
NA |
|
| 56 |
M |
IDDM not developed |
+ |
+ |
NA |
NA |
[32] |
| 46 |
F |
NA |
+ |
+ |
NA |
NA |
|
| 56 |
F |
IDDM not developed |
+ |
+ |
NA |
NA |
|
| NA |
NA |
NA |
+ |
+ |
NA |
NA |
[33] |
| NA |
NA |
NA |
+ |
+ |
NA |
NA |
|
IDDM, insulin-dependent diabetes mellitus; IAA, insulin autoantibodies; GAD-SD, GAD antibody-spectrum disorders; NA, not applicable.
a T cells displayed some reactivity to IA-2.
We cannot exclude the possibility that this patient developed GAD-SD independently of the HCT. However, the development of GAD-SD within a few years of HCT suggests that this association is unlikely to be coincidental.
In summary, we described a second patient who developed GAD-SD and T1DM following allogeneic HCT. This patient exhibited markedly elevated anti-GAD antibody levels and achieved good glucose control with a relatively small dose of insulin. Further research, including on additional cases, is required to elucidate the pathogenic mechanisms underlying this condition.
Acknowledgments
This study was supported by a grant from the Shizuoka Children’s Hospital.
Disclosure
The authors declare no conflicts of interest related to this report.
Informed Consent
Informed consent was obtained from the patient for publication of this case report.
References
- 1 Gagnon MM, Savard M (2016) Limbic encephalitis associated with GAD65 antibodies: brief review of the relevant literature. Can J Neurol Sci 43: 486–493.
- 2 Wendt A, Birnir B, Buschard K, Gromada J, Salehi A, et al. (2004) Glucose inhibition of glucagon secretion from rat alpha-cells is mediated by GABA released from neighboring beta-cells. Diabetes 53: 1038–1045.
- 3 Kawasaki E (2014) Type 1 diabetes and autoimmunity. Clin Pediatr Endocrinol 23: 99–105.
- 4 Solimena M, Folli F, Denis-Donini S, Comi GC, Pozza G, et al. (1988) Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med 318: 1012–1020.
- 5 Dalakas MC (2022) Stiff-person Syndrome and GAD Antibody-spectrum disorders: GABAergic neuronal excitability, immunopathogenesis and update on antibody therapies. Neurotherapeutics 19: 832–847.
- 6 Bai L, Ren H, Liang M, Lu Q, Lin N, et al. (2022) Neurological disorders associated with glutamic acid decarboxylase 65 antibodies: Clinical spectrum and prognosis of a cohort from China. Front Neurol 13: 990553.
- 7 Heneberg P (2023) Diabetes in stiff-person syndrome. Trends Endocrinol Metab 34: 640–651.
- 8 Majhail NS, Chitphakdithai P, Logan B, King R, Devine S, et al. (2015) Significant improvement in survival after unrelated donor hematopoietic cell transplantation in the recent era. Biol Blood Marrow Transplant 21: 142–150.
- 9 Hahn T, McCarthy PL Jr, Hassebroek A, Bredeson C, Gajewski JL, et al. (2013) Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol 31: 2437–2449.
- 10 Gabriel M, Hoeben BAW, Uhlving HH, Zajac-Spychala O, Lawitschka A, et al. (2021) A review of acute and long-term neurological complications following haematopoietic stem cell transplant for paediatric acute lymphoblastic leukaemia. Front Pediatr 9: 774853.
- 11 Dalakas MC, Li M, Fujii M, Jacobowitz DM (2001) Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology 57: 780–784.
- 12 Tsiortou P, Alexopoulos H, Dalakas MC (2021) GAD antibody-spectrum disorders: progress in clinical phenotypes, immunopathogenesis and therapeutic interventions. Ther Adv Neurol Disord 14: 17562864211003486.
- 13 Disserol CCD, Kowacs DP, Nabhan SK, Teive HAG, Kowacs PA (2023) Case report: successful autologous hematopoietic stem cell transplantation in a patient with GAD antibody-spectrum disorder with rapidly progressive dementia. Front Neurol 14: 1254981.
- 14 Hümmert MW, Stadler M, Hambach L, Gingele S, Bredt M, et al. (2021) Severe allo-immune antibody-associated peripheral and central nervous system diseases after allogeneic hematopoietic stem cell transplantation. Sci Rep 11: 8527.
- 15 Madlener M, Strippel C, Thaler FS, Doppler K, Wandinger KP, et al. (2023) Glutamic acid decarboxylase antibody-associated neurological syndromes: clinical and antibody characteristics and therapy response. J Neurol Sci 445: 120540.
- 16 Muñoz-Lopetegi A, de Bruijn M, Boukhrissi S, Bastiaansen AEM, Nagtzaam MMP, et al. (2020) Neurologic syndromes related to anti-GAD65: clinical and serologic response to treatment. Neurol Neuroimmunol Neuroinflamm 7: e696.
- 17 Graus F, Saiz A, Dalmau J (2020) GAD antibodies in neurological disorders - insights and challenges. Nat Rev Neurol 16: 353–365.
- 18 Teshima T, Boelens JJ, Matsuoka KI (2023) Novel insights into GVHD and immune reconstitution after allogeneic hematopoietic cell transplantation. Blood Cell Ther 6: 42–48.
- 19 Watkins B, Williams KM (2022) Controversies and expectations for the prevention of GVHD: a biological and clinical perspective. Front Immunol 13: 1057694.
- 20 Yamamura S, Fukui T, Mori Y, Hayashi T, Yamamoto T, et al. (2019) Circulating anti-glutamic acid decarboxylase-65 antibody titers are positively associated with the capacity of insulin secretion in acute-onset type 1 diabetes with short duration in a Japanese population. J Diabetes Investig 10: 1480–1489.
- 21 Fourlanos S, Neal A, So M, Evans A (2014) Latent autoimmune diabetes in Stiff-Person Syndrome. Diabetes Care 37: e214–e215.
- 22 Daw K, Ujihara N, Atkinson M, Powers AC (1996) Glutamic acid decarboxylase autoantibodies in stiff-man syndrome and insulin-dependent diabetes mellitus exhibit similarities and differences in epitope recognition. J Immunol 156: 818–825.
- 23 Björk E, Velloso LA, Kämpe O, Karlsson FA (1994) GAD autoantibodies in IDDM, stiff-man syndrome, and autoimmune polyendocrine syndrome type I recognize different epitopes. Diabetes 43: 161–165.
- 24 Clow EC, Couban S, Grant IA (2008) Stiff-person syndrome associated with multiple myeloma following autologous bone marrow transplantation. Muscle Nerve 38: 1649–1652.
- 25 Shargian-Alon L, Raanani P, Rozovski U, Siegal T, Yust-Katz S, et al. (2019) Immune mediated cerebellar ataxia: an unknown manifestation of graft-versus-host disease. Acta Haematol 141: 19–22.
- 26 Nagai K, Maekawa T, Terashima H, Kubota M, Ishiguro A (2019) Severe anti-GAD antibody-associated encephalitis after stem cell transplantation. Brain Dev 41: 301–304.
- 27 Sequeira M, Lobo GG, Ferro M, Capela C (2024) Relapsing remitting encephalomyelitis with glutamic acid decarboxylase antibodies following autologous haematopoietic stem cell transplantation-coincidence or consequence? Neurol Sci 45: 813–815.
- 28 Rathore GS, Leung KS, Muscal E (2015) Autoimmune encephalitis following bone marrow transplantation. Pediatr Neurol 53: 253–256.
- 29 Lee YY, Chen IW, Chen ST, Wang CC (2019) Association of stiff-person syndrome with autoimmune endocrine diseases. World J Clin Cases 7: 2942–2952.
- 30 McKeon A, Robinson MT, McEvoy KM, Matsumoto JY, Lennon VA, et al. (2012) Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol 69: 230–238.
- 31 Morgenthaler NG, Seissler J, Achenbach P, Glawe D, Payton M, et al. (1997) Antibodies to the tyrosine phosphatase-like protein IA-2 are highly associated with IDDM, but not with autoimmune endocrine diseases or stiff man syndrome. Autoimmunity 25: 203–211.
- 32 Martino G, Grimaldi LM, Bazzigaluppi E, Passini N, Sinigaglia F, et al. (1996) The insulin-dependent diabetes mellitus-associated ICA 105 autoantigen in stiff-man syndrome patients. J Neuroimmunol 69: 129–134.
- 33 Christie MR, Genovese S, Cassidy D, Bosi E, Brown TJ, et al. (1994) Antibodies to islet 37k antigen, but not to glutamate decarboxylase, discriminate rapid progression to IDDM in endocrine autoimmunity. Diabetes 43: 1254–1259.
