Myxedema Coma in Neuronal Ceroid Lipofuscinosis Type 6: a life-threatening complication in a rare disease

Myxedema Coma in Neuronal Ceroid Lipofuscinosis Type 6: a life-threatening complication in a rare disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Myxedema Coma in Neuronal Ceroid Lipofuscinosis Type 6: a life-threatening complication in a rare disease Ans Ahmed Mahmood, Sarah Imran Zahid, Ayham Khan Ansari, Abdulrahman Ahmad Zafer Issa, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8233042/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background Myxedema coma is a rare endocrine emergency with high mortality. Its occurrence in adolescents is exceptionally rare. Neuronal Ceroid Lipofuscinosis Type 6 (CLN6), commonly known as Batten disease, is a fatal genetic pediatric neurodegenerative disorder. While neurological symptoms dominate, associated endocrinopathies are not well-characterized. This report describes the first case of myxedema coma in an adolescent with CLN6 disease. Case presentation A 16-year-old male with end-stage CLN6 disease (confirmed homozygous CLN6 deletion), ventilator-dependent and in a persistent vegetative state, was transferred with acute abdominal distension, facial swelling, bradycardia (58 bpm), and hypothermia (36.2°C). He had known central hypothyroidism. Admission labs confirmed profound hypothyroidism (TSH 0.015 mIU/L, fT4 7.7 pmol/L). Abdominal CT revealed colonic pseudo-obstruction. A diagnosis of myxedema coma was made. He was treated successfully with intravenous levothyroxine and stress-dose hydrocortisone, the latter due to a borderline ACTH stimulation test suggesting adrenal insufficiency. Conclusions This case illustrates that patients with severe neurodegenerative disorders like CLN6 are at risk for life-threatening endocrine emergencies. Central hypothyroidism in this context can precipitate myxedema coma, a diagnosis complicated by the patient's underlying neurological baseline. Proactive endocrine surveillance is crucial in this population to prevent catastrophic outcomes. Myxedema Coma CLN6 Batten Disease Neuronal Ceroid Lipofuscinosis Central Hypothyroidism Rare Disease Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Myxedema coma represents the most extreme manifestation of hypothyroidism, a medical emergency with mortality rates historically reported between 25–60% [ 1 ]. It is characterized by altered mental status, hypothermia, bradycardia, and evidence of multi-organ decompensation. While it predominantly affects elderly females, its occurrence in the pediatric and adolescent population is extraordinarily rare [ 2 ]. CLN6 disease is a form of Neuronal Ceroid Lipofuscinosis (NCL), commonly known as Batten disease. It is an autosomal recessive, lysosomal storage disorder caused by mutations in the CLN6 gene, leading to progressive neurodegeneration, drug-resistant epilepsy, and premature death [ 3 ]. The management is primarily palliative. The intersection of these two rare conditions has not been previously documented. We present the first known case of myxedema coma in an adolescent with end-stage CLN6 disease. This case highlights a critical diagnostic challenge and expands the known spectrum of systemic complications in this neurodegenerative disorder, a finding highly relevant to the rare disease community. Case presentation The patient was a 16-year-old male of consanguineous Middle Eastern descent (Fig. 1 - parents were first cousins). His early development was normal until age 4–5, when he began to experience progressive neuroregression. After a prolonged diagnostic odyssey, whole genome sequencing confirmed a diagnosis of CLN6 disease with a pathogenic homozygous deletion in the CLN6 gene. A family history revealed a similarly affected brother who had succumbed to the disease. By adolescence, his condition was end-stage. He was in a persistent vegetative state, ventilator-dependent via tracheostomy, and received nutrition and medications via a gastrostomy tube. His complex medical problems included multi-drug resistant epilepsy and central hypothyroidism, managed with levothyroxine 200 mcg daily. The patient was transferred from a long-term care facility due to worsening abdominal distension and new-onset facial swelling. On admission, he was critically ill. Vital signs revealed significant bradycardia (58 bpm) and hypothermia (36.2°C). Physical examination revealed marked facial and tongue edema (myxedema) and a tense, grossly distended abdomen. His neurological status was unchanged from his baseline. The clinical presentation was highly suggestive of myxedema coma, based on hypothermia and bradycardia. Diagnostic investigations confirmed this, with Thyroid function tests showing profound central hypothyroidism (Table 1 ); TSH was 0.015 mIU/L and fT4 was 7.7 pmol/L. An ACTH stimulation test showed a borderline response (peak cortisol 416 nmol/L), suggesting concomitant adrenal insufficiency. An abdominal CT scan revealed significantly distended large bowel loops filled with fluid and without a transition point, consistent with colonic pseudo-obstruction (Ogilvie's syndrome). Table 1 Highlighting thyroid function test results Value Reference range Unit TSH 0.015 0.530–3.590 mIU/L Free triidothyronine (FT3) 2.03 3.50–7.70 pmol/L Free thyroxine (FT4) 7.7 12.0-20.6 pmol/L Additional findings included collapsed small-bowel loops till the terminal ileum containing dense food particles, and fecal loading in the rectum and sigmoid colon (Fig. 2 ). CT soft tissue neck showed soft tissue edema on either side of the neck and in the upper anterior chest bilaterally (Figure. 3). A CT brain was also performed which showed diffuse atrophic changes in the bilateral cerebral hemispheres and cerebellum, significant ventriculomegaly (left greater than the right), moderate mucosal thickening in the bilateral ethmoid air cells, sphenoid sinuses and bilateral maxillary sinuses, as well as complete opacification of bilateral middle ear cavities and mastoid air cells (Fig. 4 ). Management was initiated by a multidisciplinary team. Intravenous Levothyroxine was administered to correct the thyroid hormone deficit and Stress-Dose Hydrocortisone (100 mg IV every 8 hours) was given empirically to prevent an adrenal crisis. The patient responded favorably. His abdominal distension, facial swelling, bradycardia, and hypothermia resolved. He was stabilized and discharged back to his long-term care facility. The discharge plan emphasized strict adherence to levothyroxine and included a protocol for stress-dose steroids during future acute illnesses. Discussion This report describes the first known occurrence of myxedema coma in a patient with CLN6 Batten disease. The diagnosis was particularly challenging as the patient's profoundly depreciated neurological baseline masked the classic sign of "altered mental status." Clinicians had to rely on other key features; hypothermia, bradycardia, and distinctive myxedematous facies, to make the diagnosis [ 4 ]. The presence of colonic pseudo-obstruction, an uncommon but well-described complication of severe hypothyroidism, further provided supporting clinical evidence for a decompensated thyroid state [ 5 , 6 , 7 ]. Myxedema coma is a rare, life-threatening manifestation of severe hypothyroidism, traditionally associated with untreated primary thyroid disease in older adults [ 4 ]. However, in patients with complex neurological disorders, secondary or central hypothyroidism must also be considered when progressive hypothalamic or pituitary dysfunction is possible. Neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage neurodegenerative diseases that primarily target cortical and subcortical neurons, but neuropathology and animal models demonstrate involvement of deeper hypothalamic and other subcortical nuclei in some NCL subtypes [ 8 ]. Progressive destruction or dysfunction of hypothalamic neurons (and/or pituitary regulatory pathways) can produce secondary (central) hypothyroidism due to reduced hypothalamic TRH or pituitary TSH drive. Although endocrine manifestations in CLN6 have not been extensively catalogued, experimental studies (including CLN6 animal models) have documented hypothalamic neuronal loss and disruption of neuroendocrine circuits, providing a plausible mechanistic basis for hypothalamic–pituitary dysfunction in human CLN6 disease [ 8 , 9 ]. Given this, clinicians should consider screening for central hypothalamic–pituitary endocrinopathies in patients with progressive NCL. Diagnosing myxedema coma in patients with profound baseline neurological impairment presents unique clinical challenges. In typical presentations, altered sensorium is the dominant clinical clue signaling decompensated hypothyroidism [ 10 ]. In this case, however, the patient’s advanced neurological baseline made mental-status assessment impossible. As a result, clinicians were forced to rely on objective physiological signs, such as hypothermia, bradycardia, hypotension, and characteristic myxedematous facies, alongside targeted endocrine evaluation. This observation underscores a critical point for clinicians managing patients with severe cognitive or developmental disabilities, that established clinical heuristics and diagnostic pathways may be unreliable or unusable in this population. Instead, recognition of evolving changes in vital signs, metabolic parameters, and systemic organ function must drive early suspicion. This case also highlights the importance of gastrointestinal manifestations as supporting evidence. Severe hypothyroidism can lead to gastrointestinal atony and, in rare circumstances, acute colonic pseudo-obstruction [ 5 , 6 , 7 ]. The patient’s development of Ogilvie-type pseudo-obstruction in the absence of mechanical obstruction was consistent with longstanding reports of paralytic ileus and colonic dilation in untreated hypothyroidism. Resolution with thyroid hormone replacement and supportive bowel management further supports this association. In complex neurological patients, such gastrointestinal complications are frequently misattributed to immobility, medication effects, or primary gastrointestinal pathology, delaying endocrine evaluation and treatment. Recognizing pseudo-obstruction as a potential manifestation of endocrine decompensation is therefore clinically valuable. Beyond the individual diagnostic and therapeutic lessons, this case has broader implications for the rare-disease community. As supportive care improves, individuals with CLN6 and other neurodegenerative lysosomal storage disorders are living longer, creating opportunities for novel secondary complications to emerge [ 11 , 12 ]. As survival extends, new phenotypes including neuroendocrine failure may appear, particularly in diseases where hypothalamic or pituitary infiltration, dysfunction, or neuronal loss is biologically plausible. Accordingly, this case supports a proactive and structured approach to longitudinal management. Routine screening of thyroid function and when abnormalities are detected, cortisol and pituitary evaluation should be considered in patients with CLN6, particularly those demonstrating unexpected physiological deterioration. Furthermore, clinicians working with patients who have profound cognitive impairment must maintain a heightened index of suspicion for systemic pathology even in the absence of patient-reported symptoms. Subtle changes in baseline thermoregulation, bowel habit, heart rate, respiratory status, or metabolic laboratory results may represent the earliest or only recognizable indicators of critical endocrine failure. Conclusion This case broadens the recognized phenotype of CLN6 disease by demonstrating that profound hypothalamic–pituitary dysfunction and life-threatening endocrine crises such as myxedema coma may occur as part of its natural history. It highlights the need for ongoing, structured endocrine monitoring in patients with severe neurodegenerative conditions, particularly as advances in supportive care continue to extend survival. Importantly, clinicians must maintain a heightened clinical vigilance for systemic deterioration even when traditional diagnostic cues, such as changes in mental status, are obscured by underlying neurological impairment. This report contributes valuable clinical knowledge to the rare disease field and reinforces that optimal management of rare, progressive disorders requires a multidisciplinary perspective that anticipates secondary systemic complications rather than focusing solely on the primary neurological disease. Declarations Acknowledgements The authors would like to express our sincere gratitude to the patient and his parents for their cooperation and allowing us to share their case for academic purposes. Authors’ contributions AAM - Conceptualisation, Data collection, Writing Report and Prepared figure 1. SIZ - Data collection and Writing Report. AKA - Writing Report and Prepared figures 2,3 and 4. AAZI - Writing Report, Reviewing and Editing. KSK - Advised on the clinical aspects of the case Funding This article received no funding. Data availability No datasets were generated or analysed during the current study. Ethics approval and consent to participate Written informed consent was obtained from the patient's legal guardian for publication of this case report and any accompanying images. Consent for publication Written informed consent was obtained from the parents regarding the publication of data and photographs. Competing interests The authors declare no competing interests. References Mathew V, Misgar RA, Ghosh S, Mukhopadhyay P, Roychowdhury P, Pandit K, Mukhopadhyay S, Chowdhury S. Myxedema coma: a new look into an old crisis. J Thyroid Res. 2011;2011:493462. 10.4061/2011/493462 . De Sanctis V, Soliman A, Daar S, Di Maio S, Alhumaidi N, Alali M, Sabt A, Kattamis C. The myxedema coma in children and adolescents: a rare endocrine emergency—personal experience and review of literature. Acta Biomed. 2021;92(5):e2021481. 10.23750/abm.v92i5.12252 . Malik K, Santucci K, Sremba L et al. Neuronal Ceroid Lipofuscinoses overview. 2001 Oct 10 [Updated 2025 May 29]. In: Adam MP, Bick S, Mirzaa GM., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1428/ Zhang Y, Chu L, Han H. Myxedema coma: challenges and future directions, a systematic survey and review. Thyroid Res. 2025;18(1):48. 10.1186/s13044-025-00268-1 . Yanamandra U, Kotwal N, Menon A, Nair V. Ogilvie's syndrome in a case of myxedema coma. Indian J Endocrinol Metab. 2012;16(3):447–9. 10.4103/2230-8210.95710 . Mounce S, Kim SH, Waymack J. Ogilvie syndrome in the setting of myxedema ileus: a case report. Clin Pract Cases Emerg Med. 2025;9(4):451–3. 10.5811/cpcem.47381 . Chhabra G, Heckroth MA, Shine A, Parajuli D. S1810 myxedema pseudo-volvulus: a rare cause of acute colonic pseudo-obstruction. Am J Gastroenterol. 2021;116(Suppl):S797–8. 10.14309/01.ajg.0000780772.10487.87 . Kay GW, Jay NP, Palmer DN. The specific loss of GnRH-positive neurons from the hypothalamus of sheep with CLN6 neuronal ceroid lipofuscinosis occurs without glial activation and has only minor effects on reproduction. Neurobiol Dis. 2011;41(3):614–23. 10.1016/j.nbd.2010.11.008 . Simonati A, Williams RE. Neuronal ceroid lipofuscinosis: the multifaceted approach to the clinical issues—an overview. Front Neurol. 2022;13:811686. 10.3389/fneur.2022.811686 . Chaker L, Papaleontiou M. Hypothyroidism: a review. JAMA. 2025;334(19):1750–60. 10.1001/jama.2025.13559 . Wang XQ, Chen CB, Zhao WJ, Fu GB, Zhai Y. Rare adult neuronal ceroid lipofuscinosis associated with CLN6gene mutations: a case report. World J Clin Cases. 2023;11(15):3533–41. 10.12998/wjcc.v11.i15.3533 . Chen B, Liu Y, Cai N, Wang N, Yang K. A novel homozygous CLN6 Tyr142Cys variant in a nonconsanguineous family with Kufs disease. Neurol Sci. 2024;45(9):4597–600. 10.1007/s10072-024-07579-5 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 06 Apr, 2026 Reviewers agreed at journal 24 Mar, 2026 Reviewers invited by journal 16 Dec, 2025 Editor assigned by journal 30 Nov, 2025 Submission checks completed at journal 30 Nov, 2025 First submitted to journal 28 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":5919,"visible":true,"origin":"","legend":"\u003cp\u003ePedigree chart of the patient\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8233042/v1/36201a5c28d2bb36ea89be35.png"},{"id":98758470,"identity":"8fab3612-6856-4de3-8289-aba253648916","added_by":"auto","created_at":"2025-12-22 09:40:19","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":508029,"visible":true,"origin":"","legend":"\u003cp\u003eCT Abdomen and Pelvis with contrast (axial view) showing distended large bowel loops filled with fluid and collapsed small-bowel loops till the terminal ileum containing dense food particles and faecal loading in the rectum and sigmoid colon\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8233042/v1/aa912ff2c4ac4811d18f6917.jpeg"},{"id":98758452,"identity":"77db0e5a-9a6a-4142-905c-abc1dd527d43","added_by":"auto","created_at":"2025-12-22 09:40:18","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":259787,"visible":true,"origin":"","legend":"\u003cp\u003eCT soft tissue neck with contrast (coronal view) showing soft tissue edema on either side of the neck and in the upper anterior chest bilaterally\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8233042/v1/e5c072c5450bf72c5eb2b415.jpeg"},{"id":98758441,"identity":"fb7f7d04-f9d2-492a-86e1-e5c58c86f972","added_by":"auto","created_at":"2025-12-22 09:40:17","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":263968,"visible":true,"origin":"","legend":"\u003cp\u003eNon-contrast CT brain showing ventricular enlargement, more pronounced on the left side, along with cerebellar atrophy. Moderate mucosal thickening in the bilateral ethmoid air cells, sphenoid sinuses and bilateral maxillary sinuses, as well as complete opacification of bilateral middle ear cavities and mastoid air cells, findings consistent with Neuronal Ceroid Lipofuscinosis Type 6.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8233042/v1/cdd5c670d9dd45851cd41406.jpeg"},{"id":98758609,"identity":"41203cca-42b0-408b-b4cc-0fa6c9af019e","added_by":"auto","created_at":"2025-12-22 09:40:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1445129,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8233042/v1/8762e710-6d43-4474-8a8a-e35870e0c408.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Myxedema Coma in Neuronal Ceroid Lipofuscinosis Type 6: a life-threatening complication in a rare disease","fulltext":[{"header":"Background","content":"\u003cp\u003eMyxedema coma represents the most extreme manifestation of hypothyroidism, a medical emergency with mortality rates historically reported between 25\u0026ndash;60% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It is characterized by altered mental status, hypothermia, bradycardia, and evidence of multi-organ decompensation. While it predominantly affects elderly females, its occurrence in the pediatric and adolescent population is extraordinarily rare [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCLN6 disease is a form of Neuronal Ceroid Lipofuscinosis (NCL), commonly known as Batten disease. It is an autosomal recessive, lysosomal storage disorder caused by mutations in the CLN6 gene, leading to progressive neurodegeneration, drug-resistant epilepsy, and premature death [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The management is primarily palliative.\u003c/p\u003e \u003cp\u003eThe intersection of these two rare conditions has not been previously documented. We present the first known case of myxedema coma in an adolescent with end-stage CLN6 disease. This case highlights a critical diagnostic challenge and expands the known spectrum of systemic complications in this neurodegenerative disorder, a finding highly relevant to the rare disease community.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThe patient was a 16-year-old male of consanguineous Middle Eastern descent (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e - parents were first cousins). His early development was normal until age 4\u0026ndash;5, when he began to experience progressive neuroregression. After a prolonged diagnostic odyssey, whole genome sequencing confirmed a diagnosis of CLN6 disease with a pathogenic homozygous deletion in the CLN6 gene. A family history revealed a similarly affected brother who had succumbed to the disease.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBy adolescence, his condition was end-stage. He was in a persistent vegetative state, ventilator-dependent via tracheostomy, and received nutrition and medications via a gastrostomy tube. His complex medical problems included multi-drug resistant epilepsy and central hypothyroidism, managed with levothyroxine 200 mcg daily.\u003c/p\u003e \u003cp\u003eThe patient was transferred from a long-term care facility due to worsening abdominal distension and new-onset facial swelling. On admission, he was critically ill. Vital signs revealed significant bradycardia (58 bpm) and hypothermia (36.2\u0026deg;C). Physical examination revealed marked facial and tongue edema (myxedema) and a tense, grossly distended abdomen. His neurological status was unchanged from his baseline.\u003c/p\u003e \u003cp\u003eThe clinical presentation was highly suggestive of myxedema coma, based on hypothermia and bradycardia. Diagnostic investigations confirmed this, with Thyroid function tests showing profound central hypothyroidism (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e); TSH was 0.015 mIU/L and fT4 was 7.7 pmol/L. An ACTH stimulation test showed a borderline response (peak cortisol 416 nmol/L), suggesting concomitant adrenal insufficiency. An abdominal CT scan revealed significantly distended large bowel loops filled with fluid and without a transition point, consistent with colonic pseudo-obstruction (Ogilvie's syndrome).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHighlighting thyroid function test results\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference range\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUnit\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.530\u0026ndash;3.590\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003emIU/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFree triidothyronine (FT3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.50\u0026ndash;7.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epmol/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFree thyroxine (FT4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.0-20.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epmol/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAdditional findings included collapsed small-bowel loops till the terminal ileum containing dense food particles, and fecal loading in the rectum and sigmoid colon (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). CT soft tissue neck showed soft tissue edema on either side of the neck and in the upper anterior chest bilaterally (Figure. 3). A CT brain was also performed which showed diffuse atrophic changes in the bilateral cerebral hemispheres and cerebellum, significant ventriculomegaly (left greater than the right), moderate mucosal thickening in the bilateral ethmoid air cells, sphenoid sinuses and bilateral maxillary sinuses, as well as complete opacification of bilateral middle ear cavities and mastoid air cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eManagement was initiated by a multidisciplinary team. Intravenous Levothyroxine was administered to correct the thyroid hormone deficit and Stress-Dose Hydrocortisone (100 mg IV every 8 hours) was given empirically to prevent an adrenal crisis. The patient responded favorably. His abdominal distension, facial swelling, bradycardia, and hypothermia resolved. He was stabilized and discharged back to his long-term care facility. The discharge plan emphasized strict adherence to levothyroxine and included a protocol for stress-dose steroids during future acute illnesses.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis report describes the first known occurrence of myxedema coma in a patient with CLN6 Batten disease. The diagnosis was particularly challenging as the patient's profoundly depreciated neurological baseline masked the classic sign of \"altered mental status.\" Clinicians had to rely on other key features; hypothermia, bradycardia, and distinctive myxedematous facies, to make the diagnosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The presence of colonic pseudo-obstruction, an uncommon but well-described complication of severe hypothyroidism, further provided supporting clinical evidence for a decompensated thyroid state [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMyxedema coma is a rare, life-threatening manifestation of severe hypothyroidism, traditionally associated with untreated primary thyroid disease in older adults [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, in patients with complex neurological disorders, secondary or central hypothyroidism must also be considered when progressive hypothalamic or pituitary dysfunction is possible. Neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage neurodegenerative diseases that primarily target cortical and subcortical neurons, but neuropathology and animal models demonstrate involvement of deeper hypothalamic and other subcortical nuclei in some NCL subtypes [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Progressive destruction or dysfunction of hypothalamic neurons (and/or pituitary regulatory pathways) can produce secondary (central) hypothyroidism due to reduced hypothalamic TRH or pituitary TSH drive. Although endocrine manifestations in CLN6 have not been extensively catalogued, experimental studies (including CLN6 animal models) have documented hypothalamic neuronal loss and disruption of neuroendocrine circuits, providing a plausible mechanistic basis for hypothalamic\u0026ndash;pituitary dysfunction in human CLN6 disease [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Given this, clinicians should consider screening for central hypothalamic\u0026ndash;pituitary endocrinopathies in patients with progressive NCL.\u003c/p\u003e \u003cp\u003eDiagnosing myxedema coma in patients with profound baseline neurological impairment presents unique clinical challenges. In typical presentations, altered sensorium is the dominant clinical clue signaling decompensated hypothyroidism [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In this case, however, the patient\u0026rsquo;s advanced neurological baseline made mental-status assessment impossible. As a result, clinicians were forced to rely on objective physiological signs, such as hypothermia, bradycardia, hypotension, and characteristic myxedematous facies, alongside targeted endocrine evaluation. This observation underscores a critical point for clinicians managing patients with severe cognitive or developmental disabilities, that established clinical heuristics and diagnostic pathways may be unreliable or unusable in this population. Instead, recognition of evolving changes in vital signs, metabolic parameters, and systemic organ function must drive early suspicion.\u003c/p\u003e \u003cp\u003eThis case also highlights the importance of gastrointestinal manifestations as supporting evidence. Severe hypothyroidism can lead to gastrointestinal atony and, in rare circumstances, acute colonic pseudo-obstruction [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The patient\u0026rsquo;s development of Ogilvie-type pseudo-obstruction in the absence of mechanical obstruction was consistent with longstanding reports of paralytic ileus and colonic dilation in untreated hypothyroidism. Resolution with thyroid hormone replacement and supportive bowel management further supports this association. In complex neurological patients, such gastrointestinal complications are frequently misattributed to immobility, medication effects, or primary gastrointestinal pathology, delaying endocrine evaluation and treatment. Recognizing pseudo-obstruction as a potential manifestation of endocrine decompensation is therefore clinically valuable.\u003c/p\u003e \u003cp\u003eBeyond the individual diagnostic and therapeutic lessons, this case has broader implications for the rare-disease community. As supportive care improves, individuals with CLN6 and other neurodegenerative lysosomal storage disorders are living longer, creating opportunities for novel secondary complications to emerge [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. As survival extends, new phenotypes including neuroendocrine failure may appear, particularly in diseases where hypothalamic or pituitary infiltration, dysfunction, or neuronal loss is biologically plausible.\u003c/p\u003e \u003cp\u003eAccordingly, this case supports a proactive and structured approach to longitudinal management. Routine screening of thyroid function and when abnormalities are detected, cortisol and pituitary evaluation should be considered in patients with CLN6, particularly those demonstrating unexpected physiological deterioration. Furthermore, clinicians working with patients who have profound cognitive impairment must maintain a heightened index of suspicion for systemic pathology even in the absence of patient-reported symptoms. Subtle changes in baseline thermoregulation, bowel habit, heart rate, respiratory status, or metabolic laboratory results may represent the earliest or only recognizable indicators of critical endocrine failure.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case broadens the recognized phenotype of CLN6 disease by demonstrating that profound hypothalamic\u0026ndash;pituitary dysfunction and life-threatening endocrine crises such as myxedema coma may occur as part of its natural history. It highlights the need for ongoing, structured endocrine monitoring in patients with severe neurodegenerative conditions, particularly as advances in supportive care continue to extend survival. Importantly, clinicians must maintain a heightened clinical vigilance for systemic deterioration even when traditional diagnostic cues, such as changes in mental status, are obscured by underlying neurological impairment. This report contributes valuable clinical knowledge to the rare disease field and reinforces that optimal management of rare, progressive disorders requires a multidisciplinary perspective that anticipates secondary systemic complications rather than focusing solely on the primary neurological disease.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express our sincere gratitude to the patient and his parents for their cooperation and allowing us to share their case for academic purposes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAAM - Conceptualisation, Data collection, Writing Report and Prepared figure 1.\u003c/p\u003e\n\u003cp\u003eSIZ - Data collection and Writing Report.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAKA - Writing Report and Prepared figures 2,3 and 4.\u003c/p\u003e\n\u003cp\u003eAAZI - Writing Report, Reviewing and Editing.\u003c/p\u003e\n\u003cp\u003eKSK - Advised on the clinical aspects of the case\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis article received no funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient's legal guardian for publication of this case report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the parents regarding the publication of data and photographs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMathew V, Misgar RA, Ghosh S, Mukhopadhyay P, Roychowdhury P, Pandit K, Mukhopadhyay S, Chowdhury S. 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Neurol Sci. 2024;45(9):4597\u0026ndash;600. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10072-024-07579-5\u003c/span\u003e\u003cspan address=\"10.1007/s10072-024-07579-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Journal of Rare Diseases](https://link.springer.com/journal/44162)","snPcode":"44162","submissionUrl":"https://submission.nature.com/new-submission/44162/3","title":"Journal of Rare Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Myxedema Coma, CLN6, Batten Disease, Neuronal Ceroid Lipofuscinosis, Central Hypothyroidism, Rare Disease","lastPublishedDoi":"10.21203/rs.3.rs-8233042/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8233042/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMyxedema coma is a rare endocrine emergency with high mortality. Its occurrence in adolescents is exceptionally rare. Neuronal Ceroid Lipofuscinosis Type 6 (CLN6), commonly known as Batten disease, is a fatal genetic pediatric neurodegenerative disorder. While neurological symptoms dominate, associated endocrinopathies are not well-characterized. This report describes the first case of myxedema coma in an adolescent with CLN6 disease.\u003c/p\u003e\u003ch2\u003eCase presentation\u003c/h2\u003e \u003cp\u003eA 16-year-old male with end-stage CLN6 disease (confirmed homozygous CLN6 deletion), ventilator-dependent and in a persistent vegetative state, was transferred with acute abdominal distension, facial swelling, bradycardia (58 bpm), and hypothermia (36.2\u0026deg;C). He had known central hypothyroidism. Admission labs confirmed profound hypothyroidism (TSH 0.015 mIU/L, fT4 7.7 pmol/L). Abdominal CT revealed colonic pseudo-obstruction. A diagnosis of myxedema coma was made. He was treated successfully with intravenous levothyroxine and stress-dose hydrocortisone, the latter due to a borderline ACTH stimulation test suggesting adrenal insufficiency.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis case illustrates that patients with severe neurodegenerative disorders like CLN6 are at risk for life-threatening endocrine emergencies. Central hypothyroidism in this context can precipitate myxedema coma, a diagnosis complicated by the patient's underlying neurological baseline. Proactive endocrine surveillance is crucial in this population to prevent catastrophic outcomes.\u003c/p\u003e","manuscriptTitle":"Myxedema Coma in Neuronal Ceroid Lipofuscinosis Type 6: a life-threatening complication in a rare disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-22 09:38:35","doi":"10.21203/rs.3.rs-8233042/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-06T04:06:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"219306370300049932252802172978895771217","date":"2026-03-24T07:31:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-16T08:58:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-01T01:19:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-01T01:17:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Rare Diseases","date":"2025-11-28T19:50:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Journal of Rare Diseases](https://link.springer.com/journal/44162)","snPcode":"44162","submissionUrl":"https://submission.nature.com/new-submission/44162/3","title":"Journal of Rare Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"114e9979-6e25-429b-b3db-fa79ead988d2","owner":[],"postedDate":"December 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-22T09:38:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-22 09:38:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8233042","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8233042","identity":"rs-8233042","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}