Proximal Lower Limb Weakness Research Articles

MEN1 syndrome presents as Cushing’s disease with proximal lower limb weakness: A rare phenomenon

Abstract The typical presentation of MEN 1 syndrome in most cases is primary hyperparathyroidism. The manifestation of hypercortisolism due to a functional Pituitary microadenoma in an adult as the first presenting feature in MEN 1 is rare. This report of Cushing’s disease presenting as proximal muscle weakness due to an adrenocorticotrophic hormone (ACTH) producing pituitary microadenoma as the initial feature of multiple endocrine neoplasia type 1 is an unusual occurrence. The patient had presented with proximal muscle weakness of lower limbs along with abdominal striae and uncontrolled diabetes. On hematological and radiological evaluations, she was detected to have a pituitary microadenoma along with a parathyroid adenoma causing increased levels of ACTH, serum (S) cortisol, parathyroid hormone, and S calcium. The patient underwent a transsphenoidal decompression of the pituitary microadenoma using frameless neuronavigation. Within 2 weeks of surgery, the patient achieved normal levels of S cortisol. She is off medication for blood sugar control. At 6 months, follow-up, she is symptom-free.

SORD-related peripheral neuropathy in a French and Swiss cohort: Clinical features, genetic analyses, and sorbitol dosages.

Biallelic variants in SORD have been reported as one of the main recessive causes for hereditary peripheral neuropathies such as Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary motor neuropathy (dHMN) resulting in lower limb (LL) weakness and muscular atrophy. In this study, phenotype and genotype landscapes of SORD-related peripheral neuropathies were described in a French and Swiss cohort. Serum sorbitol dosages were used to classify SORD variants. Patients followed at neuromuscular reference centres in France and Switzerland were ascertained. Sanger sequencing and next generation sequencing were performed to sequence SORD, and mass spectrometry was used to measure patients' serum sorbitol. Thirty patients had SORD peripheral neuropathy associating LL weakness with muscular atrophy, foot deformities (87%), and sometimes proximal LL weakness (20%) or distal upper limb weakness (50%). Eighteen had dHMN, nine had CMT2, and three had intermediate CMT. Most of them had a mild or moderate disease severity. Sixteen carried a homozygous c.757delG (p.Ala253Glnfs*27) variant, and 11 carried compound heterozygous variants, among which four variants were not yet reported: c.403C > G, c.379G > A, c.68_100 + 1dup, and c.850dup. Two unrelated patients with different origins carried a homozygous c.458C > A variant, and one patient carried a new homozygous c.786 + 5G > A variant. Mean serum sorbitol levels were 17.01 mg/L ± 8.9 SD for patients carrying SORD variants. This SORD-inherited peripheral neuropathy cohort of 30 patients showed homogeneous clinical presentation and systematically elevated sorbitol levels (22-fold) compared to controls, with both diagnostic and potential therapeutic implications.

Variants in DTNA cause a mild, dominantly inherited muscular dystrophy.

DTNA encodes α-dystrobrevin, a component of the macromolecular dystrophin-glycoprotein complex (DGC) that binds to dystrophin/utrophin and α-syntrophin. Mice lacking α-dystrobrevin have a muscular dystrophy phenotype, but variants in DTNA have not previously been associated with human skeletal muscle disease. We present 12 individuals from four unrelated families with two different monoallelic DTNA variants affecting the coiled-coil domain of α-dystrobrevin. The five affected individuals from family A harbor a c.1585G > A; p.Glu529Lys variant, while the recurrent c.1567_1587del; p.Gln523_Glu529del DTNA variant was identified in the other three families (family B: four affected individuals, family C: one affected individual, and family D: two affected individuals). Myalgia and exercise intolerance, with variable ages of onset, were reported in 10 of 12 affected individuals. Proximal lower limb weakness with onset in the first decade of life was noted in three individuals. Persistent elevations of serum creatine kinase (CK) levels were detected in 11 of 12 affected individuals, 1 of whom had an episode of rhabdomyolysis at 20years of age. Autism spectrum disorder or learning disabilities were reported in four individuals with the c.1567_1587 deletion. Muscle biopsies in eight affected individuals showed mixed myopathic and dystrophic findings, characterized by fiber size variability, internalized nuclei, and slightly increased extracellular connective tissue and inflammation. Immunofluorescence analysis of biopsies from five affected individuals showed reduced α-dystrobrevin immunoreactivity and variably reduced immunoreactivity of other DGC proteins: dystrophin, α, β, δ and γ-sarcoglycans, and α and β-dystroglycans. The DTNA deletion disrupted an interaction between α-dystrobrevin and syntrophin. Specific variants in the coiled-coil domain of DTNA cause skeletal muscle disease with variable penetrance. Affected individuals show a spectrum of clinical manifestations, with severity ranging from hyperCKemia, myalgias, and exercise intolerance to childhood-onset proximal muscle weakness. Our findings expand the molecular etiologies of both muscular dystrophy and paucisymptomatic hyperCKemia, to now include monoallelic DTNA variants as a novel cause of skeletal muscle disease in humans.

Unique Clinical, Radiological and Histopathological Characteristics of a Southeast Asian Cohort of Patients with Limb-Girdle Muscular Dystrophy 2G/LGMD-R7-Telethonin-Related.

We describe a cohort of five patients with limb-girdle muscular dystrophy (LGMD) 2G/LGMD-R7 in a South-east Asian cohort. LGMD2G/LGMD-R7-telethonin-related is caused by mutations in the TCAP gene that encodes for telethonin. We identified consecutive patients with LGMD2G/LGMD-R7-telethonin-related, diagnosed at the National Neuroscience Institute (NNI) and National University Hospital (NUH) between January 2000 and June 2021. At onset, three patients presented with proximal lower limb weakness, one patient presented with Achilles tendon contractures, and one patient presented with delayed gross motor milestones. At last follow up, three patients had a limb girdle pattern of muscle weakness and two had a facioscapular humeral pattern of weakness. Whole body muscle MRI performed for one patient with a facioscapular-humeral pattern of weakness showed a pattern of muscle atrophy similar to facioscapular-humeral dystrophy. One patient had histological features consistent with myofibrillar myopathy; electron microscopy confirmed the disruption of myofibrillar architecture. One patients also had reduced staining to telethonin antibody on immunohistochemistry. We report the unique clinical and histological features of a Southeast Asian cohort of five patients with LGMD2G/LGMD-R7-telethonin-related muscular dystrophy and further expand its clinical and histopathological spectrum.

Neuromyelitis optica presenting as neurogenic bladder

Neuromyelitis optica (NMO) is an immune mediated disease of central nervous system primarily affecting optic nerves, spinal cord and brain stem. This case report describes a 24-year-old male with no comorbidities presented with high grade fever followed by proximal lower limb weakness and bilateral hydrouretero nephrosis without any lower urinary tract obstruction. He had clinical features of conus- cauda lesion with MRI spine showing features of longitudinally extensive transverse myelitis (LETM) and brain MRI showing involvement of splenium of corpus callosum. He improved with steroid therapy with in a period of 2 weeks and oral steroid was tapered of and stopped within a period of two months. There was no relapse of symptoms so far.

Case of anti‐NT5c1A antibody‐seropositive inclusion body myositis associated with severe dysphagia and prominent forearm weakness

AbstractWe report a case of an 82‐year‐old woman with inclusion body myositis (IBM), who presented with severe dysphagia, finger flexor weakness, and respiratory dysfunction. In addition, the patient showed prominent forearm weakness with quadriceps sparing and was seropositive for the anti‐cytosolic 5′‐nucleotidase 1A (NT5c1A) antibody. The presence of the anti‐NT5c1A antibody is presumably associated with dysphagia. We speculate that the anti‐NT5c1A antibody is associated with the large discrepancy between distal upper limb weakness and proximal lower limb weakness in IBM.

P.157 Dominant HSPB6 mutation in a myopathy patient

HSPB6 (also known as Hsp20) is a small heat-shock protein (sHSP) showing highest expression is skeletal, cardiac and smooth muscles. In contrast to most sHSPs, HSPB6 does not readily assemble into large oligomers on its own. However, it heterodimerizes with HSPB1 and hetero-oligomerizes with HSPB1 and αB-crystallin (CRYAB, HSPB5), modulating their oligomer size and chaperone activity. HSPB6 may also be involved in BAG3-mediated autophagy. Mutations in several sHSPs lead to neuromuscular disease. While rare missense variants in <i>HSPB6</i> have been associated with cardiomyopathy, the gene has not been previously linked to skeletal muscle disease. We describe the likely pathogenic heterozygous <i>HSPB6</i> variant c.464delC (p.Pro155Argfs*25) in a 62-year-old man with onset of the disease at 43 years of age characterized by a proximal lower limb weakness and a respiratory insufficiency. At 60 years of age, he walks with 2 canes. Of note, he underwent a cataract surgery at 28 years of age. The single-nucleotide deletion causes a frameshift predicted to replace of the six C-terminal amino acid residues of the HSPB6 protein with 24 erroneous residues. Western blotting of patient biopsy showed the normal and extended HSPB6 proteins at a 50:50 ratio, indicating that the mutant protein is expressed and stable. Histological findings included infrequent central HSPB6 accumulation in the myofibers, and myotilin-positive cytoplasmic bodies. In cell culture experiments, mutant HSPB6 showed reduced solubility compared to the wild-type protein and affected the solubility of coexpressed wild-type HSPB6, HSPB1 and CRYAB. Immunofluorescence microscopy revealed altered CRYAB localization patterns in cells expressing mutant HSPB6. Our results suggest that the <i>HSPB6</i> c.464delC (p.Pro155Argfs*25) mutation may cause muscle disease through a gain-of-function mechanism interfering with the sHSP machinery.

P226 Bortezomib-induced muscle toxicity mimicking myositis

Abstract Background/Aims Novel drugs such as bortezomib are proteasome inhibitors that are used to treat multiple myeloma. Bortezomib induces apoptosis of rapidly dividing, metabolically active cells with extensive protein synthesis. Literature review shows two case reports of bortezomib-induced reversible muscle toxicity and motor neuropathy, used to treat multiple myeloma (MM) with persistently normal creatine kinase. In a single-centre prospective study, 14 out of 24 patients with symptomatic MM were treated with bortezomib and, among these, seven developed proximal lower limb weakness with complete resolution of symptoms after discontinuation of bortezomib as depicted in our case. We present a case of myositis mimic which was triggered by the use of immunotherapy Bortezomib to treat multiple myeloma. Methods An 81-year-old Caucasian gentleman was admitted with proximal lower limb weakness. He had a background history of multiple myeloma, treated with melphalan, prednisolone and bortezomib commenced in September 2019. Following his fourth cycle in January 2020, he noted proximal lower limb weakness and was referred to Rheumatology. He had MRI of the spine which did not reveal any cord compression. His prednisolone was stopped. On further questioning, there were no features to suggest connective tissue disease, inflammatory arthritis or vasculitis. On examination power was reduced to 4/5 in the proximal muscles of lower limb affecting his mobility. Rest of the examination was unremarkable. Results All bloods including creatinine kinase, autoimmune profile and inflammatory markers were normal. Magnetic resonance imaging (MRI) of the thighs showed diffuse fatty atrophy within all muscle groups of the thighs with low grade oedema within the vastus lateralis and intermedius particularly of the left thigh when compared to the right. The appearances were in keeping with inflammatory myositis, without any abscess formation. Electromyography showed abnormal signals with neurogenic and myopathic changes. Nerve conduction studies showed moderate length-dependent axonal peripheral neuropathy. Following his review, investigations and discussion between Rheumatology and Haematology, it was believed that his lower limb weakness was likely related to his bortezomib and the decision was made to stop bortezomib therapy. He was followed up in Rheumatology and Haematology clinic after stopping bortezomib with improvement of lower limb weakness and mobility. His creatinine kinase and inflammatory markers remained persistently normal. Muscle biopsy was not considered as there was enough evidence to suggest it was bortezomib induced muscle toxicity. Conclusion We present a case of myositis mimic whose symptoms completely resolved on stopping bortezomib. As this is one of the rare and early complications of bortezomib we suggest that patients treated with bortezomib should be monitored for muscle weakness. Disclosure G. Ansari: None. Z. Alkutobi: None. A. Nandagudi: None.

Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India.

Calpainopathy is caused by mutations in the CAPN3 . There is only one clinical and genetic study of CAPN3 from India and none from South India. A total of 72 (male[M]:female [F] = 34:38) genetically confirmed probands from 72 independent families are included in this study. Consanguinity was present in 54.2%. The mean age of onset and duration of symptoms are 13.5 ± 6.4 and 6.3 ± 4.7 years, respectively. Positive family history occurred in 23.3%. The predominant initial symptoms were proximal lower limb weakness (52.1%) and toe walking (20.5%). At presentation, 97.2% had hip girdle weakness, 69.4% had scapular winging, and 58.3% had contractures. Follow-up was available in 76.4%, and 92.7% were ambulant at a mean age of 23.7 ± 7.6 years and duration of 4.5 years, remaining 7.3% became wheelchair-bound at 25.5 ± 5.7 years of age (mean duration = 13.5 ± 4.6), 4.1% were aged more than 40 years (duration range = 5–20). The majority remained ambulant 10 years after disease onset. Next-generation sequencing (NGS) detected 47 unique CAPN3 variants in 72 patients, out of which 19 are novel. Missense variants were most common occurring in 59.7% (homozygous = 29; Compound heterozygous = 14). In the remaining 29 patients (40.3%), at least one suspected loss of function variant was present. Common recurrent variants were c.2051–1G > T and c.2338G > C in 9.7%, c.1343G > A, c.802–9G > A, and c.1319G > A in 6.9% and c.1963delC in 5.5% of population. Large deletions were observed in 4.2%. Exon 10 mutations accounted for 12 patients (16.7%). Our study highlights the efficiency of NGS technology in screening and molecular diagnosis of limb-girdle muscular dystrophy with recessive form (LGMDR1) patients in India.

Acute disseminated encephalomyelitis in a patient with Noonan syndrome: A rare autoinflammatory complication or coincidence?

We describe a 13-years-old girl, previously diagnosed with PTPN11-associated Noonan Syndrome (NS), who presented to the pediatric emergency department for fever and drowsiness, which gradually worsened within 48 h. On admission, brain magnetic resonance imaging (MRI) scan showed diffuse, symmetric, multiple, poorly demarcated, confluent hyperintense lesions on MRI T2w-images, located in the Central Nervous System (CNS). In the absence of a better explanation and according to the current diagnostic criteria, a diagnosis of Acute Disseminated Encephalomyelitis (ADEM) was performed. The patient was first treated with intravenous methylprednisolone, then with intravenous immunoglobulin (IVIG). Owing to the poor clinical response, three sessions of therapeutic plasma exchange (TPE) were finally performed, with a progressive improvement. Follow-up MRI performed after three months from the onset revealed a considerable reduction in brain lesions, while cervical and dorsal ones were substantially unmodified. Neurological examination showed a full recovery of cognitive function and improved strength and tone of the upper limbs, while tetrahyporeflexia and proximal weakness of lower limbs were still appreciable.To date, this is the first described case of ADEM occurring in a patient with NS.

F42. EMG findings in patients with limb-girdle muscular dystrophy due to heterozygous CAPN3 mutations

Introduction Limb-girdle muscular dystrophy type 2A (LGMD2A) is the most common autosomal recessive (AR) LGMD subtype worldwide. The disease is caused by homozygous pathogenic mutations in the calpain 3 gene (CAPN3). Although strict AR inheritance is assumed for CAPN3-related myopathies, recent reports described symptomatic patients carrying a single CAPN3 mutation. The LGMDs share common clinical and laboratory findings such as weakness and atrophy of proximal muscles, often affecting lower extremities first; elevated creatine kinase (CK) levels; and dystrophic findings on muscle biopsy. Some clinical and imaging findings help to differentiate LGMD2A, such as asymmetric weakness and atrophy and early scapular winging. On muscle MRI, calpain deficiency characteristically reveals preferential involvement of posterior thigh muscles and the adductor magnus muscle with relative sparing of the anterior thigh muscles. There are few reports on EMG findings in patients with single CAPN3 mutations. Methods Two unrelated patients with LGMD and harboring single CAPN3 mutations were identified. They underwent detailed neurological evaluation, muscle biopsy, muscle MRI and electroneuromyography (ENMG). Results Patient one: man, 28 years old, born from nonconsanguineous parents, presenting progressive calves atrophy since 24 years old. Genetic analysis showed the variant c.258dupT;p. (Leu87Serfs*4) at CAPN3 in heterozygosity. ENMG showed myopathic motor unit action potential (MUAP) on left gastrocnemius and pectoralis major, and on right biceps brachii, without fibs or positive sharp waves. Right gastrocnemius muscle biopsy showed moderate myopathic changes. Patient two: woman, 77 years old, born from nonconsanguineous parents, presenting progressive proximal lower limb weakness in the last 2 years. Genetic analysis revealed the heterozygous frameshift variant c.550delA; p. (Thr184Argfs*36) in the CAPN3 gene. ENMG showed moderate diffuse myopathy, with preferential involvement of posterior tigh muscles and gastrocnemius with fibs and positive sharp waves. MRI showed severe atrophy of posterior tight muscles. Right quadriceps femoris biopsy revealed minimal myopathic changes. Conclusion The typical clinical, imaging and electrophysiological findings from LGMD2A can be found in patients presenting heterozygous pathogenic mutations in CAPN3 gene, indicating that a dominantly inherited form of calpainopathy exists, but with a milder fenotype. EMG reveals a predominantly posterior leg pattern of involvement.

Paraneoplastic myositis: case report and review of literature

To present a rare association of squamous cell carcinoma of the tonsil with myositis with a review of similar cases reported in the literature. We present a 69-year-old male patient admitted to hospital with an 8-week history of lethargy, proximal lower limb weakness and weight loss. On systemic

Design, set-up and utility of the UK facioscapulohumeral muscular dystrophy patient registry.

Facioscapulohumeral dystrophy (FSHD) is a rare inherited neuromuscular disease estimated to affect 1/15,000 people. Through basic research, remarkable progress has been made towards the development of targeted therapies. Patient identification, through registries or other means is essential for trial-readiness. The UK FSHD Patient Registry is a patient initiated registry that collects standardised and internationally agreed dataset of self-reported clinical details combined with professionally verified genetic information. It includes four additional questionnaires to capture patient reported outcomes related to pain, quality of life and scapular fixation. Between 2013 and 2015, 518 patients registered 243 males, 241 females with a mean age of 47.8 years. Most of the patients have FSHD type 1 (91.7 %), and weakness of the facial (59.2 %) was the most prevalent symptom at onset, followed by shoulder-girdle muscles (53.3 %) and distal (22.45 %) or proximal lower limb weakness (14.8 %). 85.57 % patients were ambulant or ambulant with assistance at the time of registration, 7.9 % report respiratory insufficiency. The registry has demonstrated utility with the recruitment of patients for a natural history study of infantile onset FSHD, and the longitudinal analysis of patient-related outcomes will provide much-needed baseline information to power future trials. The internationally agreed core dataset enables national registries to participate in a “Global FSHD registry”. We suggest that the registry’s ability to interoperate with other large datasets will be instrumental for sharing and exploiting data globally.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-016-8132-1) contains supplementary material, which is available to authorized users.

G.P.173 - A novel mutation in DNAJB6 causes LGMD1D in two French families

Mutations in the co-chaperone DNAJB6 is the cause of LGMD1D (OMIM: #603511). To date, six different protein level changes have been reported (F89I, F91I, F93I, F93L, P96R, and F100I). Interestingly, all mutations are located in the G/F-rich domain of DNAJB6. The various mutations are found in families of European, American and Asian origin. We here report a novel mutation found in two French families that is also located to the G/F-domain of DNAJB6. Clinical symptoms presented between 35 and 50 years of age with proximal lower limb weakness and difficulty rising from chairs. The pathology is congruent with previously reported LGMD1D mutations with progressive loss of muscle fibers, rimmed vacuoles and cytoplasmic protein aggregates that are observed in muscle biopsies from affected muscles. In a filter-trap based system using transient transfection of mammalian cell lines and polyQ-huntingtin, which is a model for an aggregation-prone protein, the mutant protein shows significant loss of anti-aggregation capacity compared to the wild-type. DNAJB6 is part of the larger chaperonal complex system handling chaperone mediated selective autophagy. Besides the decreased anti-aggregation function of the new mutant, the functions of the whole complex as previously reported are impaired in a dominant fashion by mutant DNAJB6.

Criança com hipertrofia gemelar e elevação das transaminases: relato de caso

Introduction: Transaminases are non-specific markers of hepatocyte function. There are several conditions associated with elevated transa-minases such as Duchenne muscular dystrophy (DMD), an X-linked recessive disorder characterized by progressive muscle weakness. Case Report: We report the case of a 6 year-old boy referred to the pediatric department for evaluation of raised transaminases. He had no family history of liver or neuromuscular disease. From his past history we noted independent gait at 15 months, toe-walking, difficulty climbing stairs and running, and fatigue in comparison to his peers. On clinical examination there was calf and abdominal hypertrophy, slight lumbar lordosis, proximal lower limb weakness and a positive Gowers’ sign. Given the clinical history, physical examination and la-boratory findings, the diagnosis of muscular dystrophy was suspected. Serum creatine kinase was found to be elevated. A muscle biopsy was performed and revealed absence of dystrophin. DMD gene sequencing identified the mutation c.3103C>T (p.Gln1035X) which confirmed the diagnosis of DMD. Comment: The finding of raised transaminases is not always diagnostic of liver disease. With prolonged elevation of those enzymes, liver disease must be excluded but this laboratory finding may also appear in muscle disease. CK levels should also be measured to avoid exhaustive testing for liver disease. The authors advise clinicians to consider neuromuscular diseases in the differential diagnosis of cases presenting a with suggestive clinical and laboratory findings.

Progressive bilateral facial weakness

A 72-year-old man presented with sudden onset of right-sided facial muscle weakness and slurred speech and a 3-day history of fevers, myalgia and sore throat. There was no hyperacusis, change...

Proximal Lower-Limb Weakness in Charcot-Marie-Tooth Disease—Reply

Proximal Lower-Limb Weakness in Charcot-Marie-Tooth Disease—Reply

Lipid storage myopathy with clinical markers of Marfan syndrome: A rare association

Disorders of lipid metabolism can cause variable clinical presentations, often involving skeletal muscle, alone or together with other tissues. A 19-year-old boy presented with a 2-year history of muscle pain, cramps, exercise intolerance and progressive weakness of proximal lower limbs. Examination revealed skeletal markers of Marfan syndrome in the form of increased arm span compared with height, Kyphoscoliois, moderate pectus excavatum, high arched palate and wrist sign. He also had mild neck flexor weakness and proximal lower limb weakness with areflexia. Pathologic findings revealed lipid-laden fine vacuoles in the muscle fibers. Possibility of carnitine deficiency myopathy was considered and the patient was started on carnitine and Co Q. The patient made remarkable clinical improvement over the next 2 months. This case is reported for rarity of the association of clinical markers of Marfan syndrome and lipid storage myopathy and sparse literature on lipid storage myopathy in the Indian context.

Atypical onset in a series of 122 cases with FacioScapuloHumeral Muscular Dystrophy

IntroductionFacioScapuloHumeral Muscular Dystrophy (FSHD), a disease linked to a heterozygous D4Z4 deletion on chromosome 4q35, typically starts with shoulder-girdle and facial muscle involvement. Atypical presentations have occasionally been reported, but their frequency has still not been defined. Patients and methodsWe studied the occurrence rate of FSHD with atypical onset in 122 symptomatic subjects from 76 unrelated families with genetically confirmed FSHD. These 75 males and 47 females, with a mean age of 49 years (range: 11–85), had a mean EcoRI fragment of 25kb (range: 11–38). ResultsTypical shoulder-girdle or facial weakness at onset was reported by 88 patients (72%). Unusual presentations included: foot drop in 16 (13%) and proximal lower limb weakness in eight patients (7%). Two cases at onset manifested quite atypical, apparently non-FSHD-related syndromes: a 42-year-old woman presented with infantile epilepsy and a 41-year-old man with myoglobinuria. In the latter patient, DNA analysis detected a 4q35 deletion associated to an heterozygous CAPN3 mutation. ConclusionFSHD presentation with foot drop or lower limb proximal weakness appeared to be more frequent than expected. This type of weakness at onset has to be considered premature, but still representative of disease-related muscle involvement. Quite atypical onset appears very rare and calls for further investigation on non-FSHD-related etiology.

A Rare Case of Thyrotoxic Periodic Paralysis Presenting to the Medical Examiner

Thyrotoxic periodic paralysis is a rare and dramatic complication of hyperthyroidism. Thyrotoxic periodic paralysis classically presents with proximal lower limb weakness in the setting of hypokalemia and thyrotoxicosis. Thyrotoxic periodic paralysis represents an endocrine emergency with a rapidly ascending paralysis that can result in respiratory insufficiency, cardiac arrhythmias, and death if not accurately and rapidly diagnosed. We report a case of undiagnosed fatal thyrotoxic periodic paralysis presenting to the medical examiner. The diagnosis was made primarily by review of the clinical history.