Comprehensive analysis of m6A regulators characterized by the immune microenvironment in Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked, incurable, degenerative neuromuscular disease that is exacerbated by secondary inflammation. N6-methyladenosine (m6A), the most common base modification of RNA, has pleiotropic immunomodulatory effects in many diseases. However, the role of m6A modification in the immune microenvironment of DMD remains elusive. METHODS: Our study retrospectively analyzed the expression data of 56 muscle tissues from DMD patients and 26 from non-muscular dystrophy individuals. Based on single sample gene set enrichment analysis, immune cells infiltration was identified and the result was validated by flow cytometry analysis and immunohistochemical staining. Then, we described the features of genetic variation in 26 m6A regulators and explored their relationship with the immune mircoenvironment of DMD patients through a series of bioinformatical analysis. At last, we determined subtypes of DMD patients by unsupervised clustering analysis and characterized the molecular and immune characteristics in different subgroups. RESULTS: DMD patients have a sophisticated immune microenvironment that is significantly different from non-DMD controls. Numerous m6A regulators were aberrantly expressed in the muscle tissues of DMD and inversely related to most muscle-infiltrating immune cell types and immune response-related signaling pathways. A diagnostic model involving seven m6A regulators was established using LASSO. Furthermore, we determined three m6A modification patterns (cluster A/B/C) with distinct immune microenvironmental characteristics. CONCLUSION: In summary, our study demonstrated that m6A regulators are intimately linked to the immune microenvironment of muscle tissues in DMD. These findings may facilitate a better understanding of the immunomodulatory mechanisms in DMD and provide novel strategies for the treatment.

Next-Generation Sequencing of Cerebrospinal Fluid for the Diagnosis of VZV-Associated Rhombencephalitis.

BACKGROUND: Rhombencephalitis (RE) is a general term for a group of inflammatory diseases of the rhombencephalon caused by different etiologies. Patients of RE caused by the varicella-zoster virus (VZV) are sporadic in medical practice. The VZV-RE is easily misdiagnosed and causes a poor prognosis for patients. METHODS: In this study, we analyzed the clinical symptoms and imaging features of five patients with VZV-RE diagnosed by the next-generation sequencing (NGS) technique of cerebrospinal fluid. Magnetic resonance imaging (MRI) examination was used to characterize the imaging of the patients. The McNemar test was used to analyze the cerebrospinal fluid testing (CSF) values and MRI test of the 5 patients. RESULTS: We finally used NGS technology to confirm the diagnosis in 5 patients with VZV-RE. MRI revealed T2/FLAIR high signal lesions in the patients' medulla oblongata, pons, and cerebellum. All patients had early signs of cranial nerve palsy; some had herpes or pain in the corresponding cranial nerve distribution areas. The patients develop headaches, fever, nausea, vomiting, and other signs and symptoms of brainstem cerebellar involvement. McNemar's test showed no statistical difference between multi-mode MRI and CSF values for diagnosing VZV-RE (p = 0.513). CONCLUSIONS: This study showed that patients with herpes in the skin and mucous membranes at the distribution area of the cranial nerves and with the underlying disease were prone to RE. We suggest that the NGS analysis should be considered and selected based on the level of parameters, such as MRI lesion characteristics.

Case report: Meningoencephalocele and recurrent bacterial meningitis in chronic idiopathic intracranial hypertension.

BACKGROUND: Meningoencephalocele is a rare malformation caused by congenital and acquired lesions. The association between recurrent bacterial meningitis and meningoencephaloceles with cerebrospinal fluid (CSF) leak is reported in the literature. We report a rare case of meningoencephalocele secondary to chronic idiopathic intracranial hypertension as a result of hospitalization repeatedly for meningitis due to the lack of CSF leak. CASE PRESENTATION: This study presents a case of a patient with a decade of recurrent meningitis. With clinical symptoms and imaging examination with chronic idiopathic intracranial hypertension, this patient was diagnosed with meningoencephalocele. With the treatment of acetazolamide to decrease CSF product, the patient had no recurrence of meningitis over the 6-months follow-up period. CONCLUSION: In patients with recurrent intracranial infections but no history of immunodeficiency, cranial trauma, or neurosurgery, the possibility of meningitis should be considered appropriately, even in the absence of CSF otorrhea or rhinorrhea.

The clinical, myopathological, and molecular characteristics of 26 Chinese patients with dysferlinopathy: a high proportion of misdiagnosis and novel variants.

BACKGROUND: Dysferlinopathy is an autosomal recessive muscular dystrophy caused by pathogenic variants in the dysferlin (DYSF) gene. This disease shows heterogeneous clinical phenotypes and genetic characteristics. METHODS: We reviewed the clinical and pathological data as well as the molecular characteristics of 26 Chinese patients with dysferlinopathy screened by immunohistochemistry staining and pathogenic variants in DYSF genes. RESULTS: Among 26 patients with dysferlinopathy, 18 patients (69.2%) presented as Limb-girdle Muscular Dystrophy Type R2 (LGMD R2), 4 (15.4%) had a phenotype of Miyoshi myopathy (MM), and 4 (15.4%) presented as asymptomatic hyperCKemia. Fifteen patients (57.7%) were originally misdiagnosed as inflammatory myopathy or other diseases. Fifteen novel variants were identified among the 40 variant sites identified in this cohort. CONCLUSION: Dysferlinopathy is a clinically and genetically heterogeneous group of disorders with various phenotypes, a high proportion of novel variants, and a high rate of misdiagnosis before immunohistochemistry staining and genetic analysis.

A case of spontaneous spinal epidural hematoma mimicking transient ischemic attack.

Spontaneous spinal epidural hematoma (SSEH), a disease with exact etiology unknown, is characterized by acute onset of neck or back pain and rapidly progressive nerve root or spinal cord compression. It is rare in clinical practices, with a prevalence of approximately one in a million. Due to the lack of population-based epidemiological survey data for SSEH, clinicians have a serious lack of understanding of the disease and are prone to miss the best time for treatment, leaving patients with neurological dysfunction which is difficult to recover. In this paper, we report a case of SSEH with rare clinical manifestations, to improve clinicians' understanding of SSEH. The patient was mainly characterized by episodic left lower limb weakness and had been misdiagnosed as TIA.

The clinical, pathological, and genetic characteristics of lipid storage myopathy in northern China.

BACKGROUND: The lipid storage myopathy (LSM) diagnosis is based on the patient's clinical manifestations and muscle pathology. However, when genetic testing is lacking, there is a high rate of misdiagnosis of the disease. This study aimed to investigate the clinical and pathological features of genetically diagnosed LSM in northern China, analyze genetic mutations' characteristics, and improve the LSM diagnostic rate. METHODS: Twenty patients with LSM diagnosed were collected; meanwhile, the clinical data, muscle samples, and routine pathological staining of muscle specimens were collected. The morphological changes of muscle fibers were observed under an optical microscope. RESULTS: Among the included patients, 18 cases had ETFDH (HGNC ID: 3483) mutations, and two had PNPLA2 mutations. Family pedigree verification was performed on three patients with heterozygous mutations in the ETFDH gene complex. Histopathological staining showed that all patients had fine vacuoles in the muscle fibers, and some of them merged to form fissures, and the lipid droplets increased in cells. After therapy, 18 patients were associated with a favorable prognosis, and two patients were ineffective with the treatment of neutral lipid storage myopathy (NLSDM) caused by PNPLA2 mutation. DISCUSSION: The clinical manifestations of LSM are complex and diverse, mainly manifested by proximal muscle weakness and exercise intolerance in the extremities. The pathological images of LSM muscles are abnormal storage of lipid droplets in muscle fibers, primarily involving type I fibers. The LSM patients were mainly multiple acyl-CoA dehydrogenase deficiency (MADD) caused by the ETFDH gene mutation. It is necessary to perform an accurate typing diagnosis of LSM.

Mutation at a new allele of the dysferlin gene causes Miyoshi myopathy: A case report.

Miyoshi myopathy (MM) is a rare autosomal recessive disorder caused by dysferlin (DYSF) gene mutation. Miyoshi myopathy-inducing mutation sites in the DYSF gene have been discovered worldwide. In the present study, a patient with progressive lower extremity weakness is reported, for which MM was diagnosed according to clinical manifestations, muscle biopsy, and immunohistochemistry. In addition, the DYSF gene of the patient and his parents was sequenced and analyzed and two heterozygous mutations of the DYSF gene (c.4756C> T and c.5316dupC) were discovered. The first mutation correlated with MM while the second was a new mutation. The patient was diagnosed with a compound heterozygous mutation. The mutation site is a new member of pathogenic MM gene mutations.

A patient with acute myeloid leukemia presented with a superior sagittal sinus thrombosis as the first manifestation of Trousseau syndrome.

This paper reports a case of Trousseau syndrome with intracranial venous sinus thrombosis as the first manifestation, which is relatively rare in the clinic. A 44-year-old female patient presented with a blurred vision of the visual substance for 2 months, and the condition was aggravated with a headache for 10 days. The final diagnosis was intracranial venous sinus thrombosis and acute myeloid leukemia subtype M2. Anticoagulant + intra-arterial regimen (cytarabine + igdabistar) was given, and the patient's headache and blurred vision were gradually restored. After 2 courses of chemotherapy, acute myeloid leukemia subtype M2 was in complete remission. After 6 months of follow-up, headache and the blurred vision disappeared, leukemia did not recur, limb vascular ultrasound was screened regularly, and no new vascular embolism disease occurred.

Birt-Hogg-Dubé syndrome caused by a mutation of FLCN gene in a CVST patient: a case report.

Background: To our knowledge, this is the first report of patient with BHD syndrome caused by a novel mutation in the FLCN gene who developed a cerebral venous sinus thrombosis(CVST).Case presentation: A 62-year-old male patient with a history of hypertension and two case of spontaneous pneumothorax. He had a 1-month history of headache and was admitted to the hospital one day after the headache aggravated. The patient had a family history of BHD syndrome which was confirmed by FLCN gene sequencing. Sequencing analysis revealed a novel nonsense mutation (NM_144997; c.607A > T; p.Lys203Ter) in the FLCN gene exon 6 of the patient, which was proved to be a pathogenetic mutation by pedigree verification. BHD syndrome was finally definitive diagnosis. Low molecular weight heparin (21 days) was given for anticoagulant therapy before and after resection of renal tumor which is confirmed to be clear cell carcinoma in the kidney. After discharge, warfarin was given for anticoagulant therapy (6 months).Conclusions: There was no recurrence of CVST. And no recurrence of tumor and new renal tumor were found in renal MRI examination after 6 months.

A case of surgically-associated anti GQ1b antibody syndrome accompanied by saccadic ping pong gaze.

BACKGROUND: Periodic alternating ping-pong gaze (PPG) is a rare disease with few reports. To our knowledge, there was no report on anti GQ1b antibody syndrome accompanied by PPG. This paper reported a case of anti GQ1b antibody syndrome with Bickerstaff's Encephalitis (BBE) overlapping classic Guillain-Barre Syndrome (GBS) after aortic valve replacement, accompanied by an excessive PPG in the course of diagnosis and treatment, this was indeed rarely. CASE PRESENTATION: A 55-year-old male patient was admitted to our hospital with intermittent chest tightness for 3 months, and his condition has worsened in the past 10 days. Aortic valve replacement was performed because of the existence of the moderate and severe stenosis of aortic valve. Horizontal movement of the eyeball was involuntarily slow. The eyeball hovered and returned from one side to the other horizontally for 3-4 s per cycle. In combination with the patient's typical clinical and laboratory tests, the final diagnosis was anti GQ1b antibody syndrome BBE combined with GBS, accompanied by saccadic ping pong gaze. Intravenous immunoglobulin (0.4 g/kg) was given for immunomodulation, methylprednisolone (1000 mg) therapy and symptomatic treatment were performed in the patient. CONCLUSIONS: The patients were discharged from hospital on the thirtieth day because of economic reasons. After 6 months of follow up, the patients left behind a lack of fluency in speech and limb mobility, but the basic life can be taken care of by himself.

Adolescent Hyperuricemia with Lipid Storage Myopathy: A Clinical Study.

BACKGROUND In this study, we investigated the clinical and pathological features of patients with lipid storage myopathy (LSM) complicated with hyperuricemia, to improve clinicians' understanding of metabolic multi-muscular disorder with metabolic disorders, and to reduce the risk of missed diagnosis of LSM. MATERIAL AND METHODS From January 2005 to December 2017, 8 patients underwent muscle biopsy and diagnosed by muscle pathology and genetic testing in our hospital. All 8 patients were in compliance with LSM diagnosis. We collected data on the patient's clinical performance, adjuvant examination, treatment, and outcomes to provide a comprehensive report and description of LSM patients with hyperuricemia. RESULTS All patients were diagnosed as having ETFDH gene mutations. The main clinical manifestations of patients were chronic limb and trunk weakness, limb numbness, and muscle pain. The serum creatine kinase (CK) values in all patients were higher than normal values. Electromyography showed 3 cases of simple myogenic damage and 3 cases of neurogenic injury. Hematuria metabolic screening showed that 2 patients had elevated glutaric aciduria, and 1 patient had elevated fatty acyl carnitine in the blood. All patients were given riboflavin treatment, and the clinical symptoms were significantly improved, and 3 patients returned to normal uric acid levels after treatment. Pathological staining showed an abnormal deposition of lipid droplets in muscle fibers. CONCLUSIONS If an adolescent hyperuricemia patient has abnormal limb weakness, exercise intolerance, and elevated serum CK values, clinicians need to be highly alert to the possibility of LSM. Early diagnosis and treatment of LSM should improve the clinical symptoms and quality of life and reduce complications.

Recurrent cerebral infarction in anterior and posterior circulation territories associated with persistent primitive hypoglossal artery and carotid artery dissection: a case report.

The persistent primitive hypoglossal artery (PPHA) is the second most common persistent carotid-vertebrobasilar anastomosis. We present a rare case of an 82-year-old woman who diagnosed as acute cerebral infarction three times in both the anterior and posterior circulation territories with a right-sided PPHA and ipsilateral carotid artery dissection (CAD). Microembolus monitoring results suggested that microembolic caused by CAD associated with PPHA should be recognized as a possible cause of multiple infarctions in both the anterior and posterior circulation territories. For these patients, appropriate treatment measures should be taken for prevention of stroke recurrence.

Myelin oligodendrocyte glycoprotein antibody-associated disease with clinical presentation as multiple episodes of isolated meningeal involvement: a case report.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) constitutes a group of autoimmune neuroinflammatory conditions that are characterized by positive serum MOG-immunoglobulin G antibodies. The relationship between MOGAD and immune factors remains unclear. Herein, we report a man in his early 30s who initially presented symptoms of headache and low-grade fever persisting for 20 days. The patient experienced isolated meningitis onset and had recurrent meningitis as the primary clinical feature, which manifested as low-grade fever, headache, and neck rigidity. Although cranial magnetic resonance imaging showed no abnormalities, immunotherapy was promptly administered upon diagnosing MOGAD through positive MOG-specific antibody testing of cerebrospinal and serum fluids. Notably, the patient's symptoms exhibited rapid improvement following treatment. Although meningitis is traditionally associated with infectious diseases, it can also occur in antibody-related autoimmune diseases that affect the central nervous system. Consequently, MOGAD should be considered in cases of aseptic meningitis with an unknown etiology, to facilitate definitive diagnosis and enhance patient prognosis.

Loop PDE of viral capsid protein is involved in immune escape of the emerging novel variant infectious bursal disease virus.

Infectious bursa disease (IBD) is an acute, highly contactable, lethal, immunosuppressive infectious disease caused by the Infectious bursa disease virus (IBDV). Currently, the emerged novel variant IBDV (nVarIBDV) and the sustainedly prevalent very virulent IBDV (vvIBDV) are the two most prevalent strains of IBDV in China. The antigenic properties of the two prevalent strains differed significantly, which led to the escape of nVarIBDV from the immune protection provided by the existing vvIBDV vaccine. However, the molecular basis of the nVarIBDV immune escape remains unclear. In this study, we demonstrated, for the first time, that residues 252, 254, and 256 in the PDE of VP2 are involved in the immune escape of the emerging nVarIBDV. Firstly, the IFA-mediated antigen-antibody affinity assay showed that PBC and PDE of VP2 could affect the affinity of vvIBDV antiserum to VP2, of which PDE was more significant. The key amino acids of PDE influencing the antigen-antibody affinity were also identified, with G254N being the most significant, followed by V252I and I256V. Then the mutated virus with point or combined mutations was rescued by reverse genetics. it was further demonstrated that mutations of V252I, G254N, and I256V in PDE could individually or collaboratively reduce antigen-antibody affinity and interfere with antiserum neutralization, with G254N being the most significant. This study revealed the reasons for the widespread prevalence of nVarIBDV in immunized chicken flocks and provided innovative ideas for designing novel vaccines that match the antigen of the epidemic strain.

Analysis of Metagenomic Next-Generation Sequencing (mNGS) in the Diagnosis of Herpes Simplex Virus (HSV) Encephalitis with Normal Cerebrospinal Fluid (CSF).

Background: Metagenomic next-generation sequencing (mNGS) is becoming increasingly extensive in diagnosing herpes simplex encephalitis (HSE). However, many HSE patients with normal cerebrospinal fluid (CSF) diagnosed by mNGS have been found during the clinical application. This study aimed to summarize and analyze the clinical characteristics, supplementary examinations, and prognosis of patients with HSE whose cerebrospinal fluid was confirmed to be normal by mNGS. Methods: This retrospective study evaluated the clinical characteristics, auxiliary examinations, and patient prognosis of patients with HSE that were diagnosed by mNGS but had normal CSF. Clinical data collected included baseline information, signs and symptoms upon admission, and risk factors for infection. Auxiliary examinations included indirect immunofluorescence assay (IIF), cell-based assay (CBA), and CSF testing. Prognosis was evaluated based on hospital stay and patient survival. Results: Seven of the nine patients (77.8%) experienced headaches, and four (44.4%) had a fever of 38°C or higher. The average leukocyte count in the CSF was 2.6 ± 2.3/L. According to the mNGS, the median sequence count of HSV was 2 (1, 16). Magnetic resonance imaging (MRI) revealed one bilateral temporal lobe lesion (11.1%), two isolated bilateral frontal lobe lesions (22.2%), and one bilateral cingulate gyrus lesion (11.1%). One patient (11.1%) was admitted to the intensive care unit and passed away in the hospital. The remaining patients (88.9%) had a positive prognosis upon discharge. Conclusion: Patients with HSE who had normal CSF were typically middle-aged women with normal immune function. They showed typical HSE clinical features, such as fever, headache and epilepsy, that did not differ from those of other HSE patients. A normal CSF result is generally associated with a low viral load and the body's ability to mount an effective immune response. Most of these patients have a favorable prognosis.

Delayed gadolinium contrast-enhanced 3D-T1 SPACE STIR sequence can better visualize abnormal cranial nerves: a case report.

With the advancement of magnetic resonance imaging (MRI) techniques, general radiographic methods are no longer sufficient for accurately displaying the structure and pathway of cranial nerves. Various sequences, including 3-dimensional sampling perfection with application-optimized contrast using different flip angle evolution (SPACE), have been developed through MRI technology to effectively display the location and severity of damaged cranial nerves. This current case report describes a 36-year-old male patient with multiple cranial nerve injuries resulting from an invasive Mucor infection. While performing MRI scanning on this patient, a 1-h delayed enhanced MRI 3D-T1 SPACE short tau inversion recovery (STIR) sequence proved more effective in eliminating background interference and assessing neurological damage with greater clarity than conventional enhancement methods. This approach may prove beneficial in accurately evaluating the extent of cranial neuropathy, thus facilitating clinical applications.

Acute invasive mucormycosis rhinosinusitis causing multigroup cranial nerve injury and meningitis-A case report.

This study reported a case of a Rhino-Orbital-Cerebral Mycosis (ROCM) patient with multiple groups of cranial nerve damage as the primary clinical manifestation, confirmed by histopathology and cerebrospinal fluid metagenomic next-generation sequencing (mNGS) technology. Relying on the MRI3D-SPACE technology, we observed the location and extent of the cranial nerve damage in the patient. The results suggested that fungal meningoencephalitis caused by mucor may enter the skull retrograde along the cranial nerve perineurium. The patient was admitted to the hospital with a preliminary diagnosis of mucormycosis infection after 1.5 days of mouth deviation. We treated the patient immediately with intravenous amphotericin B liposomes. After 21 days of hospitalization, the clinical symptoms of the patient did not improve significantly. The patient was discharged due to financial difficulties and antifungal treatment at home, and his disease had stabilized at the 6-month follow-up.

Case report: A variant of wall-eyed bilateral internuclear ophthalmoplegia from unilateral pons infarction.

Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) is an uncommon ocular motility disorder that encompasses the following clinical signs: bilateral adduction deficits, bilateral abducting nystagmus, convergence lost, and a large angle exotropia in primary gaze. Here we report a case of a 55-year-old man presenting with atypical WEBINO syndrome with unilateral exotropia. The coverage test was used to record the patient's alternating exotropia. The patient experienced diplopia and ophthalmoplegia and was admitted to our hospital 3 days after the onset of the double vision. Neurologic examination showed left eye exotropia and bilateral internuclear ophthalmoplegia with impaired convergence. Vertical saccades of the left eye were also limited. Consequently, an MRI scan suggested an acute infarction in the left of the pontine tegmentum. The patient was finally diagnosed with pons infarction and was treated with anticoagulation and anti-platelet aggregation therapy.

Analysis of Cases with Cerebrospinal Fluid Characteristics Similar to Tuberculous Meningitis.

Purpose: The diagnosis of tuberculous meningitis (TBM) is difficult and relies on the patient's clinical presentation and initial cerebrospinal fluid testing. Treatment outcomes for some patients with early consideration of TBM meningitis are often poor. Patients and Methods. In this study, we retrospectively analyzed 24 non-TBM patients whose early changes of cerebrospinal fluid were similar to those of TBM through the second-generation cerebrospinal fluid sequencing technology. Results: All patients included in this study had an acute onset, including 5 patients with a history of upper respiratory tract infection, 9 patients with fever, 6 patients with headache, 5 patients with psychiatric symptoms, 6 patients with cognitive impairment, 9 patients with signs of meningeal irritation, and 6 patients with seizures. Sixteen patients presented with altered content and level of consciousness during their admission. The leukocyte counts (median, 124.0 × 106/L) and total protein concentrations (median, 1300 mg/L) were higher than normal reference values in all patients, whereas glucose (median, 1.345 mmol/L) and chloride concentration values (average, 111.7 ± 5.2 mmol/L) were lower than normal reference values. The patients included 2 cases of Liszt's meningitis, 2 cases of Brucella infection in the CNS, 4 cases of Varicella zoster virus encephalitis, 2 cases of human herpes simplex virus type 1, 2 cases of lupus encephalopathy, 2 cases of anti-NMDAR receptor encephalitis, 2 cases of meningeal carcinomatosis, 5 cases of cryptococcal meningitis, 2 cases of CNS sarcoidosis, and a case of invasive Rhizopus oryzae infection. All patients were tested for NGS in cerebrospinal fluid. Eight patients were diagnosed with anti-NMDAR encephalitis, meningeal carcinomatosis, lupus encephalopathy, and CNS sarcoidosis. Nine patients experienced death; 15 patients had a good prognosis and left no significant sequelae. Conclusion: The analysis of patients with TBM-like cerebrospinal fluid changes will help improve the diagnostic accuracy of the disease and reduce misdiagnosis and underdiagnosis.

Characterization of 31 Patients with Riboflavin-Responsive Multiple acyl-CoA Dehydrogenase Deficiency

Aims: To evaluate the clinical, pathological, and genetic features of patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD). Methods: Thirty-one patients with RR-MADD admitted to our hospital from January 2005 to November 2020 were enrolled, and their clinical data were collected. Pathological characteristics of the muscle tissue and possible pathogenic gene mutations were analyzed. Results: The most common clinical features in all patients were symmetrical proximal muscle weakness. Laboratory examination revealed elevated levels of creatine kinase, homocysteine, and uric acid, acylcarnitines, and organic acid. The muscle biopsy revealed typical pathological changes like lipid deposition. Genetic analysis identified ETFDH mutations in 29 patients, among which one had homozygotes, 19 had compound heterozygotes, 7 had heterozygous mutations, and 2 had heterozygous mutations of both ETFDH and ETFA. Two patients had no pathogenic gene mutations. All patients were treated with riboflavin, and their symptoms improved, which was consistent with the diagnosis of RR-MADD. Conclusion: The clinical manifestations and genetic test results of patients with RR-MADD are heterogeneous. Therefore, a comprehensive analysis of clinical, pathological, and genetic testing is essential for the early diagnosis of RR-MADD.