Vertical Supranuclear Gaze Palsy Research Articles

Patient-Specific iPSC-Derived Neural Differentiated and Hepatocyte-like Cells, Carrying the Compound Heterozygous Mutation p.V1023Sfs*15/p.G992R, Present the "Variant" Biochemical Phenotype of Niemann-Pick Type C1 Disease.

Niemann–Pick disease type C1 (NP-C1) is a rare lysosomal storage disorder caused by autosomal recessive mutations in the NPC1 gene. Patients display a wide spectrum on the clinical as well as on the molecular level, wherein a so-called “variant” biochemical phenotype can be observed. Here, we report an in vitro analysis of fibroblasts obtained from an NP-C1 patient carrying the undescribed compound heterozygous mutation p.V1023Sfs*15/p.G992R. Since NP-C1 is a neurovisceral disease and the patient suffers from severe neurological as well as hepatic symptoms, we extended our study to neural differentiated and hepatocyte-like cells derived from patient-specific induced pluripotent stem cells. We detected slightly increased intracellular cholesterol levels compared to the control cell line in fibroblasts, neural differentiated and hepatocyte-like cells, suggesting a “variant” biochemical phenotype. Furthermore, the total NPC1 protein, as well as post-ER glycoforms of the NPC1 protein, tended to be reduced. In addition, colocalization analysis revealed a mild reduction of the NPC1 protein in the lysosomes. The patient was diagnosed with NP-C1 at the age of 34 years, after an initial misdiagnosis of schizophrenia. After years of mild and unspecific symptoms, such as difficulties in coordination and concentration, symptoms progressed and the patient finally presented with ataxia, dysarthria, dysphagia, vertical supranuclear gaze palsy, and hepatosplenomegaly. Genetic testing finally pointed towards an NP-C1 diagnosis, revealing the so-far undescribed compound heterozygous mutation p.V1023Sfs*15/p.G992R in the NPC1 gene. In light of these findings, this case provides support for the p.G992R mutation being causative for a “variant” biochemical phenotype leading to an adult-onset type of NP-C1 disease.

Eye-of-the-Tiger Sign with an Unexpected Pathological Diagnosis.

Clinical diagnosis of atypical parkinsonisms may be challenging. The eye-of-the-tiger sign on brain MRI, typical of neurodegeneration with brain iron accumulation, has been anecdotally observed in cases clinically diagnosed as atypical parkinsonisms. To show how clinical syndromes and even neuroimaging sometimes may lead the neurologist to a misunderstanding, just as to emphasize the important role of pathology to establish the final diagnosis in these cases. Clinico-pathological case. A 67-year-old-woman presented with progressive painful stiffness and allodynia in her left arm. On examination, she presented parkinsonism without tremor with greater involvement of left limbs. She developed dystonia, with myoclonic tremor and hypoesthesia involving her left arm, as well as an impairment of balance with falls, a significant axial involvement with disabling rigidity, supranuclear gaze abnormalities, facial dystonia, dysphonia, severe dysphagia, and anarthria. There was no response to levodopa. Syndromic diagnosis and findings on neuroimaging are discussed. Afterwards, the underlying pathology is revealed. We present the first case of neuropathologically confirmed multiple system atrophy with the eye-of-the-tiger sign on brain MRI. The presence of supranuclear vertical gaze palsy further complicated a correct clinical diagnosis. A pathological postmortem study remains essential to establish a definite diagnosis in atypical parkinsonisms.

Niemann\u2013Pick disease type C in Palestine: genotype and phenotype of sixteen patients and report of a novel mutation in the NPC1 gene

BackgroundNiemann–Pick disease type C (NPC) is an autosomal recessive, neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. Mutations in these genes are associated with abnormal endosomal–lysosomal trafficking, resulting in the accumulation of tissue-specific lipids in lysosomes.MethodsWe described sixteen patients with NPC diagnosed between the age of 1 month and 30 years at two tertiary care centers in Palestine. The clinical phenotype, brain magnetic resonance imaging (MRI), and molecular genetic analysis data were reviewed.ResultsThe diagnosis was confirmed by molecular analysis in all patients. Fourteen out of sixteen patients were homozygous for the NPC1 p.G992W variant. Among them, most were categorized as having the late-infantile neurological form of disease onset. They predominantly manifested with early-onset visceral manifestations in the form of hepatosplenomegaly and prolonged neonatal jaundice, and late-onset neuropsychiatric manifestations in the form of vertical supranuclear gaze palsy (VSGP), ataxia, cognitive impairment and seizures. Brain MRI in 6 patients was normal in 5 or consistent with cerebellar hemisphere atrophy in 1 of them. Two other mutations were identified in the NPC1 gene, of which p.V845Cfs*24 was novel.ConclusionsOur results revealed phenotypic heterogeneity of NPC even within the same genotype, and add to the increasingly recognized evidence that cholestatic jaundice and hepatosplenomegaly during infancy, should alert the physician for the possibility of NPC. We reported a novel mutation in the NPC1 gene further expanding its genotype.

Spectrum of Movement Disorders of Late-Onset Niemann-Pick Disease Type C

Niemann-Pick disease type C (NPC), is a rare lysosomal storage disorder, which has a variable presentation based on the age of onset. We describe five adult/adolescent-onset NPC cases presenting with a range of movement disorders along with vertical supranuclear gaze palsy as part of the clinical presentation. A diagnostic delay of 4-17 years from the symptom onset was found in this case series. A high index of clinical suspicion in adult/adolescent patients presenting with vertical supranuclear gaze palsy along with various movement disorder phenomenology can help in the early diagnosis of NPC.

Vertical saccadic palsy and foveal retinal thinning in Niemann-Pick disease type C.

IntroductionNiemann-Pick type C (NPC) is a lysosomal storage disease that is progressive and life-limiting, with an estimated incidence of 1:120,000 live births. In addition to systemic manifestation with (hepato-)splenomegaly, there are a number of neurological manifestations (ataxia, dysarthria, dementia, cataplexy, epileptic seizures, and psychiatric disorders). Characteristic is vertical supranuclear gaze palsy, which is often overlooked. Early diagnosis and start of therapy improve quality of life. This study aimed to characterize oculomotor dysfunction of NPC patients, and to provide ophthalmologic data including retinal imaging.MethodsEighteen patients with biochemically or genetically diagnosed NPC completed oculomotor and ophthalmologic examination. Ten of them performed saccadometry by infrared based video-oculography. Saccadic parameters were compared to 100 healthy controls, and were correlated with clinical variables. Another subgroup of eight patients received optical coherence tomography (OCT) of the optic disc and the macula, of which the segmented layers were analysed using a crude linear mixed model, and one adjusted for age, sex, and spherical equivalent.ResultsSaccadometry revealed slowed peak velocity compared to controls most evident vertically. Peak velocity correlated negatively with SARA-Score, but correlation with clinical assessment of saccades was not significant. Clinical features in the assessment of vertical saccades were intensive blinking and head movements to initiate gaze changes, and lateral trajectory of the eyes. Macular OCT revealed significant total retinal thinning in the fovea, specifically of the outer nuclear layer and outer retinal layer. Para- and perifoveal retinal thicknesses, as well as peripapillary retinal nerve fibre layer were normal.ConclusionsFoveal thinning was revealed in NPC. It remains to be shown, whether OCT will prove to be useful to monitor progression. Saccadic impairment reflects CNS involvement and therefore is a parameter to demonstrate the progression of NPC, and potentially also the efficacy of new therapies. Saccadometry, in contrast to clinical investigation, allows the precise evaluation of saccades.

Environmental Risk Factors for Progressive Supranuclear Palsy.

Typically, progressive supranuclear palsy (PSP) is clinically characterized by slow vertical saccades or supranuclear gaze palsy, levodopa-resistant parkinsonism with predominant axial symptoms, and cognitive executive impairment. Over the past decades, various PSP phenotypes, including PSP with predominant parkinsonism, PSP with corticobasal syndrome, PSP with progressive gait freezing, and PSP with predominant frontal dysfunction, have been identified from pathologically confirmed cases. Expanding knowledge led to new diagnostic criteria for PSP that with increased disease awareness led to increased PSP prevalence estimates. The identification of environmental and modifiable risk factors creates an opportunity to intervene and delay the onset of PSP or slow disease progression. To date, despite the increasing number of publications assessing risk factors for PSP, few articles have focused on environmental and lifestyle risk factors for this disorder. In this article, we reviewed the literature investigating the relationship between PSP and several environmental and other modifiable lifestyle risk factors. In our review, we found that exposures to toxins related to diet, metals, well water, and hypertension were associated with increased PSP risk. In contrast, higher education and statins may be protective. Further case-control studies are encouraged to determine the exact role of these factors in the etiopathogenesis of PSP, which in turn would inform strategies to prevent and reduce the burden of PSP.

Dream Enactment Behavior Disorder Associated with Pallido-Nigro-Luysian Degeneration and Tau Proteinopathy.

Pallido-nigro-luysian atrophy (PNLA) is a rare neurodegenerative disorder with only a few cases reported to date. Although the clinical picture usually resembles progressive supranuclear palsy, pathological examination reveals more selective atrophy and loss of neurons in the globus pallidus, substantia nigra and subthalamic nucleus. To describe the clinical features and pathological findings of a patient with PNLA. Case report with clinico-pathological discussion. An 83-year-old man presented to our clinic with a vertical supranuclear gaze palsy, parkinsonism, gait impairment and sleep abnormalities suggestive of REM-sleep behavior disorder. Neuropathological examination 5 years after symptom onset revealed subcortical tau proteinopathy compatible with a PNLA pattern. There was also an associated mild degree of limbic/subcortical inflammatory response, Alzheimer's disease-related changes, as well as argyrophilic grain disease. We present a comprehensive clinico-pathological discussion of a patient with PNLA. Besides parkinsonism and vertical supranuclear gaze palsy, the patient also had a sleep disorder, clinically suggestive of REM behavioral disorder, which has not been previously reported in PNLA. We expand the clinical phenotype of this rare condition and provide neuropathological evidence for the associated abnormalities.

Progressive Supranuclear Palsy: A Case Report and Literature Review

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease with a prevalence of five to six persons per 100,000 people and characterized by progressive axial rigidity, vertical supranuclear gaze palsy, frontal lobe cognitive decline, and balance issues. The clinical examination findings are diverse and PSP cases are often under-diagnosed or misdiagnosed. We report a case of a 54- year-old male patient that presented primarily with recurrent falls due to postural instability and bilateral leg weakness that had progressively worsened to being wheelchair-bound. An extensive physical examination revealed classical findings indicative of PSP.

Hashimoto's encephalopathy presenting with cognitive impairment and vertical supranuclear gaze palsy

Hashimoto's encephalopathy presenting with cognitive impairment and vertical supranuclear gaze palsy

Association of MRI Measures With Disease Severity and Progression in Progressive Supranuclear Palsy.

Objective: To verify the association of midbrain-based MRI measures as well as cortical volumes with disease core features and progression in patients with Progressive Supranuclear Palsy (PSP).Methods: Sixty-seven patients (52.2% with Richardson's syndrome) were included in the present analysis. Available midbrain-based MRI morphometric assessments as well as cortical lobar volumes were computed. Ocular, gait and postural involvement at the time of MRI was evaluated with the PSP rating scale. Specific milestones or death were used to estimate disease progression up to 72 months follow up. Hierarchical regression models and survival analysis were used for analyzing cross-sectional and longitudinal data, respectively.Results: Multivariate models showed vertical supranuclear gaze palsy was associated with smaller midbrain area (OR: 0.02, 95% CI 0.00–0.175, p = 0.006). Cox regression adjusted for age, disease duration, and phenotype demonstrated that lower midbrain area (HR: 0.122, 95% CI 0.030–0.493, p = 0.003) and diameter (HR: 0.313, 95% CI 0.112–0.878, p = 0.027), higher MR Parkinsonism Index (HR: 6.162, 95% CI 1.790–21.209, p = 0.004) and larger third ventricle width (HR: 2.755, 95% CI 1.068–7.108, p = 0.036) were associated with higher risk of dependency on wheelchair.Conclusions: Irrespective of disease features and other MRI parameters, reduced midbrain size is significantly associated with greater ocular motor dysfunction at the time of MRI and more rapid disease progression over follow up. This is the first comprehensive study to systematically assess the association of available midbrain-based MRI measures and cortical volumes with disease severity and progression in a large cohort of patients with PSP in a real-world setting.

Genetics of Progressive Supranuclear Palsy: A Review.

Progressive supranuclear palsy (PSP) is an atypical parkinsonism with prominent 4R-tau neuropathology, and the classical clinical phenotype is characterized by vertical supranuclear gaze palsy, unprovoked falls, akinetic-rigid syndrome and cognitive decline. Though PSP is generally regarded as sporadic, there is increasing evidence suggesting that a series of common and rare genetic variants impact on sporadic and familial forms of PSP. To date, more than 10 genes have been reported to show a potential association with PSP. Among these genes, the microtubule-associated protein tau (MAPT) is the risk locus with the strongest effect size on sporadic PSP in the case-control genome-wide association studies (GWAS). Additionally, MAPT mutations are the most common cause of familial PSP while the leucine-rich repeat kinase 2 (LRRK2) is a rare monogenic cause of PSP, and several other gene mutations may mimic the PSP phenotype, like the dynactin subunit 1 (DCTN1). In total, 15 MAPT mutations have been identified in cases with PSP, and the mean age at onset is much earlier than in cases carrying LRRK2 or DCTN1 mutations. GWAS have further identified several risk loci of PSP, proposing molecular pathways related to PSP. The present review focused on genetic studies on PSP and summarized genetic factors of PSP, which may help to elucidate the underlying pathogenesis and provide new perspectives for therapeutic strategies.

Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease.

Niemann Pick disease type C (NPC) is a neurovisceral disorder due to mutations in NPC1 or NPC2. This review focuses on poorly characterized clinical and molecular features of early infantile form of NPC (EIF) and identified 89 cases caused by NPC1 (NPC1) and 16 by NPC2 (NPC2) mutations. Extra-neuronal features were common; visceromegaly reported in 80/89 NPC1 and in 15/16 NPC2, prolonged jaundice in 30/89 NPC1 and 7/16 NPC2. Early lung involvement was present in 12/16 NPC2 cases. Median age of neurological onset was 12 (0–24) and 7.5 (0–24) months in NPC1 and NPC2 groups, respectively. Developmental delay and hypotonia were the commonest first detected neurological symptoms reported in 39/89 and 18/89 NPC1, and in 8/16 and 10/16 NPC2, respectively. Additional neurological symptoms included vertical supranuclear gaze palsy, dysarthria, cataplexy, dysphagia, seizures, dystonia, and spasticity. The following mutations in homozygous state conferred EIF: deletion of exon 1+promoter, c.3578_3591 + 9del, c.385delT, p.C63fsX75, IVS21-2delATGC, c. 2740T>A (p.C914S), c.3584G>T (p.G1195V), c.3478-6T>A, c.960_961dup (p.A321Gfs*16) in NPC1 and c.434T>A (p.V145E), c.199T>C (p.S67P), c.133C>T (p.Q45X), c.141C>A (p.C47X) in NPC2. This comprehensive analysis of the EIF type of NPC will benefit clinical patient management, genetic counselling, and assist design of novel therapy trials.

Treatment outcomes following continuous miglustat therapy in patients with Niemann-Pick disease Type C: a final report of the NPC Registry

BackgroundNiemann-Pick disease Type C (NP-C) is a rare, progressive neurodegenerative disorder characterized by progressive neurodegeneration and premature death. We report data at closure of the NPC Registry that describes the natural history, disease course and treatment experience of NP-C patients in a real-world setting.MethodsThe NPC Registry was a prospective observational cohort study that ran between September 2009 and October 2017. Patients with a confirmed diagnosis of NP-C were enrolled regardless of treatment status. All patients underwent clinical assessments and medical care as determined by their physicians; data were collected through a secure internet-based portal.ResultsAt closure on October 19, 2017, 472 patients from 22 countries were enrolled in the NPC Registry. Mean (standard deviation) age at enrollment was 21.2 (15.0) years, and 51.9% of patients were male. First neurological symptom onset occurred during the early-infantile (< 2 years), late-infantile (2 to < 6 years), juvenile (6 to < 15 years), or adolescent/adult (≥ 15 years) periods in 13.5, 25.6, 31.8, and 29.1% of cases, respectively. The most frequent neurological manifestations prior to enrollment included ataxia (67.9%), vertical supranuclear gaze palsy (67.4%), dysarthria (64.7%), cognitive impairment (62.7%), dysphagia (49.1%), and dystonia (40.2%). During infancy, splenomegaly and hepatomegaly were frequent (n = 199/398 [50%] and n = 147/397 [37.0%], respectively) and persisted in most affected patients. Of the 472 enrolled patients, 241 were continuously treated with miglustat during the NPC Registry observation period, of whom 172 of these 241 patients were treated continuously for ≥12 months. A composite disability score that assesses impairment of ambulation, manipulation, language, and swallowing was highest in the early-infantile population and lowest in the adolescent/adult population. Among the continuous miglustat therapy population, 70.5% of patients had improved or had stable disease (at least 3 of the 4 domains having a decreased or unchanged score between enrollment and last follow-up). The NPC Registry did not identify any new safety signals associated with miglustat therapy.ConclusionsThe profiles of clinical manifestations in the final NPC Registry dataset agreed with previous clinical descriptions. Miglustat therapy was associated with a stabilization of neurological manifestations in most patients. The safety and tolerability of miglustat therapy was consistent with previous reports.

The mind’s eye: A neuro-ophthalmological perspective on Niemann-Pick type C disease

Niemann-Pick disease type C (NPC) is a rare autosomal recessive genetic disease caused by mutations in the NPC1 and NPC2 genes with an estimated incidence of 1:120 000 live births. The clinical presentations vary across the ages. Children present with visceral symptoms related to cholesterol accumulation in the liver and adults have predominantly neuropsychiatric features such as dementia. However, vertical supranuclear gaze palsy can be present from the first year of life and is a strong feature in the diagnosis of NPC, which can be confirmed by a skin biopsy. A 36-year-old female with long-standing depression was referred for an evaluation of dystonia. She had progressive cognitive decline, dysarthria, dysphonia, dystonia of the trunk and limbs, ataxia and supranuclear gaze palsy. A similar course of illness affected her brother. Her parents were first cousins. She had positive Filipin stain of fibroblasts cultured from her skin biopsy, confirming the diagnosis of NPC. Miglustat, the approved drug for treatment, was not accessible. She had been on simvastatin since diagnosis, with a poor response, and had ongoing severe cognitive and physical disability. There are few conditions that present with neuropsychiatric symptoms and supranuclear gaze palsy. This patient had been managed as chronic depression with psychosis since her teenage years and her diagnosis was reviewed only when she had developed dystonia. Supranuclear gaze palsy is an early diagnostic clinical clue that could be present from infancy and should be sought in patients with neurocognitive presentations.

Evaluation of different suspicion indices in identifying patients with Niemann-Pick disease Type C in clinical practice: a post hoc analysis of a retrospective chart review

BackgroundNiemann-Pick disease Type C (NP-C) is a lysosomal lipid storage disorder with varying symptomatology depending on the age of onset. The diagnosis of NP-C is challenging due to heterogeneous nonspecific clinical presentation of the disease. NP-C Suspicion Index (SI) was developed to aid screening and identification of patients with suspicion of NP-C for further clinical evaluation. Here we assess the performance of five NP-C SI models to identify patients with NP-C compared with clinical practice to determine the best SI model for identification of each clinical form of NP-C by age.MethodsThis was a post hoc analysis of a retrospective chart review of patient data collected from five expert NP-C centers. The study assessed the proportion of patients with NP-C who could have been identified using the Original SI, Refined SI, 2/7 SI, 2/3 SI, and Early-Onset SI and evaluated the performance of each SI against clinical practice. A score above a threshold of 70 points for the Original SI, 40 points for the Refined SI, 6 points for the Early-Onset SI, and 2 points for the 2/7 and 2/3 SIs represented identification of NP-C.ResultsThe study included 63 patients, and of these, 23.8% had a family history of NP-C. Of the available SI tools, the Refined SI performed well in identifying patients with NP-C across all age groups (77.8% infantile, 100% juvenile and 100% adult groups), and earlier identification than clinical diagnosis would have been possible in 50.0% of infantile, 72.7% of juvenile and 87.0% of adult patients. Patients who were not detected by the Refined SI prior to clinical diagnosis mainly presented with delayed developmental milestones, visceral manifestations, neurologic hypotonia, clumsiness, ataxia, vertical supranuclear gaze palsy, parent or siblings with NP-C, dysarthria/dysphagia and psychotic symptoms.ConclusionThis study demonstrated the applicability of various SI models for screening and identification of patients with NP-C for further clinical evaluation. Although NP-C is rare and the patient population is limited, this study was conducted in a real-world setting and confirms SI models as useful screening tools that facilitate identification of patients with NP-C earlier in their disease course.

Niemann-Pick type C: contemporary diagnosis and treatment of a classical disorder

Niemann-Pick type C is an uncommon neurodegenerative lysosomal storage disorder that can cause a progressive neuropsychiatric syndrome associated with supranuclear vertical gaze palsy and a movement disorder. There have been...

An Evaluation of the Progressive Supranuclear Palsy Speech/Language Variant.

The Movement Disorder Society clinical criteria for progressive supranuclear palsy (PSP) provide a framework for assessing the presence/severity of clinical symptoms and define a speech/language variant of PSP. To evaluate the clinical criteria in a cohort of speech/language patients with longitudinal follow-up. A total of 52 patients presenting with progressive apraxia of speech and/or agrammatic aphasia were followed longitudinally for up to 6 visits with clinical assessments and magnetic resonance imaging. We assessed oculomotor, postural instability, and akinesia diagnostic levels and determined whether patients met criteria for possible PSP-speech/language or probable PSP at each visit. Kaplan-Meier curves assessed time-to-event probabilities according to age. Statistical parametric mapping and midbrain volume were assessed according to disease progression. Few PSP symptoms were observed early in the disease, with oculomotor abnormalities and falls first observed 2 years after onset. Falls were more common than vertical supranuclear gaze palsy. Bradykinesia and rigidity commonly developed but axial was rarely greater than appendicular rigidity. During follow-up, 54% met criteria for possible PSP-speech/language, 38% for probable PSP-Richardson's syndrome, and 38% for probable PSP-parkinsonism, most commonly 6 to 6.9 years after onset. The probability of developing PSP was greater when onset was at an age older than 70 years. Patients who progressed to probable PSP had more parkinsonism and oculomotor impairment at baseline and greater midbrain atrophy when compared with those who did not develop probable PSP. Symptoms typical of PSP commonly develop in patients presenting with a progressive speech/language disorder. Older age appears to be an important prognostic factor in these patients.

Editors' note: IgLON5-mediated neurodegeneration is a differential diagnosis of CNS Whipple disease

In “IgLON5-mediated neurodegeneration is a differential diagnosis of CNS Whipple disease,” Morales-Briceno et al. described a case of anti-IgLON5 disease presenting as cold intolerance, myorhythmia, myoclonus, dysarthria, hypersalivation, dysphagia, sleep apnea, and mildly impaired cognition mimicking CNS Whipple disease. Drs. Bally and Lang report that the presentation in this case was similar to cases of Whipple disease in the literature; however, palatal involvement of the myorhythmia—which was present in the case reported by Morales-Briceno et al.—is rare in Whipple disease, and the cranial myorhythmia in Whipple disease is associated with a vertical supranuclear gaze palsy, which was not present in the case reported by Morales-Briceno et al. Morales-Briceno et al. respond that while the absence of vertical gaze palsy made Whipple disease less likely, such gaze palsies can occur in a certain percentage of patients with IgLON5-mediated neurodegeneration. Both Morales-Briceno et al. and Drs. Bally and Lang agree that the distinction between IgLON5-mediated neurodegeneration and Whipple disease can be challenging. In “IgLON5-mediated neurodegeneration is a differential diagnosis of CNS Whipple disease,” Morales-Briceno et al. described a case of anti-IgLON5 disease presenting as cold intolerance, myorhythmia, myoclonus, dysarthria, hypersalivation, dysphagia, sleep apnea, and mildly impaired cognition mimicking CNS Whipple disease. Drs. Bally and Lang report that the presentation in this case was similar to cases of Whipple disease in the literature; however, palatal involvement of the myorhythmia—which was present in the case reported by Morales-Briceno et al.—is rare in Whipple disease, and the cranial myorhythmia in Whipple disease is associated with a vertical supranuclear gaze palsy, which was not present in the case reported by Morales-Briceno et al. Morales-Briceno et al. respond that while the absence of vertical gaze palsy made Whipple disease less likely, such gaze palsies can occur in a certain percentage of patients with IgLON5-mediated neurodegeneration. Both Morales-Briceno et al. and Drs. Bally and Lang agree that the distinction between IgLON5-mediated neurodegeneration and Whipple disease can be challenging.

Author response: IgLON5-mediated neurodegeneration is a differential diagnosis of CNS Whipple disease.

We thank Drs. Bally and Lang for their interest in our report,1 and for alerting clinicians to the fact that palatal tremor (PT) occurs in only a minority of patients with neurologic Whipple disease (WhD). Drs. Bally and Lang also point out that PT occurred in the absence of olivary pseudohypertrophy in WhD. Interestingly, olivary pseudohypertrophy was also absent in our patient with IgLON5, as well as a patient with IgLON5 and cranial myorhythmia reported by Honorat et al.2 Drs. Bally and Lang also suggest that the absence of vertical gaze palsy makes WhD a less likely possibility. While we agree, the presence of vertical gaze palsy does not distinguish between the 2 conditions, as vertical gaze palsy is also reported in 27% of patients with IgLON5.3 The combination of myorhythmia and myoclonus in our patient was reminiscent of neurologic WhD, but the presence of sleep apnea—and eventually severe sleep disturbance—was the trigger to consider IgLON5. Both IgLON5-mediated neurodegeneration and WhD may rarely present with PT, vertical supranuclear gaze palsy, and normal MRI. While facial spasms are increasingly recognized in IgLON5,3 it may be that oculomasticatory myorhythmia is the most specific neurologic sign of WhD.4,5

Reader response: IgLON5-mediated neurodegeneration is a differential diagnosis of CNS Whipple disease.

We read with interest the case report by Morales-Briceno et al.1 of IgLON5 with cranial myorhythmia. We just completed a systematic review of movement disorders in Whipple disease (WhD) that might provide useful perspective.2 The clinical picture shown here was generally consistent with WhD and even stimulus-sensitive truncal myoclonus was once reported in WhD (our second case). However, the presence of palatal tremor (PT) is unusual for this condition.2 We found only 2 cases of palatal involvement of the myorhythmia.3,4 The authors of case 2 emphasized that the absence of typical PT should encourage a suspicion of WhD.4 Schwartz et al.5 highlighted the fact that the neuropathologic hallmark of PT, olivary pseudohypertrophy, was not found in their second patient, and Van Bogaert et al.2 repeatedly emphasized the absence of palatal involvement of the myorhythmia. Another clue to an alternative diagnosis is that all 6 WhD cases with isolated cranial myorhythmia had a concomitant vertical supranuclear gaze palsy not evident in the present case. Thus, although we agree that WhD was a reasonable consideration in the reported patient, there were clinical features that favored an alternative diagnosis, as the authors eventually discovered.