A variant in GRN of Spanish origin presenting with heterogeneous phenotypes

A. Marked depletion of motor neurons from the anterior horn of the spinal cord (H&E). B. Motor neuron filiform cytoplasmic inclusion is revealed by anti-TDP-43 in the spinal cord (black arrow). Other remaining motor neurons show loss of normal nuclear staining (red arrows). C. Many cortical neuronal small para nuclear inclusions are detected with antibodies to TDP-43 (black arrows). Short cortical dystrophic neurites are observed with anti-TDP-43 (black arrowheads) Loss of normal nuclear staining of TDP-43 is noted (red arrows). D. Some hippocampal neuronal cytoplasmic inclusions in dentate granule cells are displayed (black arrows). Loss of normal nuclear staining of TDP-43 is noted (red arrow). Magnification x400.

Introduction
The variant c.1414-1G > T in theGRN gene has been previously reported as probably pathogenic in subjects of Hispanic origin in the American continent.

Methods
We report five families of Spanish origin carrying this variant, including the clinical, neuroimaging, and laboratory findings.

Results
Phenotypes were strikingly different, including cases presenting with behavioral variant of frontotemporal dementia, with semantic variant of primary progressive aphasia, with rapidly progressive motor neuron disease (pathologically documented), and with tremor-dominant parkinsonism. Retinal degeneration has been found in homozygous carriers only. Ex vivo splicing assays confirmed that the mutation c.1414-1G > T affects the splicing of the exon, causing a loss of 20 amino acids in exon 11.

Conclusions
We conclude that variant c.1414-1G > Tn the GRN gene is pathogenic, can lead to a variety of clinical presentations and to gene dosage effect, and probably has a Spanish founder effect.

Full text: https://doi.org/10.1016/j.nrleng.2022.10.001

A series of cases with Huntington-like phenotype and intermediate repeats in HTT

Here we describe the larger series of clinical cases (n = 14) with HD-like phenotype and IAs published to date.  MRI and FDG-PET neuroimaging findings compatible with HD can be found in some patients with IA.  Larger and more detailed series are needed to assess the pathogenic role of IAs in HTT gene.

Background
Intermediate Alleles (IAs) are expansions of CAG repeats in the HTT gene between 27 and 35 repeats which pathogenic meaning remains controversial. They are present in the general population but there is an increasing number of cases with Huntington-like phenotype reported.

Methods
We reviewed the medical records of cases in our centre where the neurologist suspected Huntington's disease (HD) as one of the feasible diagnoses and genetic testing showed the number of CAG repeats was in the “intermediate range”. We gathered the type of symptoms in all cases and the main neuroimaging findings when available.

Results
We found 14 cases, 8 males and 6 females, with average age at onset at 64 years old. Most cases exhibited some type of extrapyramidal symptoms. Cognitive and/or behavioral symptoms were also present in most cases (being depression, anxiety and cognitive impairment the most frequent ones). In one case we found deposits of iron in the basal ganglia in the MRI, and in another case we found diffuse cortical hypometabolism with predominantly frontal bilateral involvement and bilateral focal deficit of both caudate and thalamus in the FDG-PET.

Conclusion
The clinical and neuroimaging findings of some cases with IA in this series are compatible with the clinical picture of HD but also with several other alternative diagnoses. Therefore we can not establish association between IA and HD. Larger series with more comprehensive diagnostic workout and neuropathological studies are needed to confirm or rule out whether IAs in the HTT gene may cause HD.

DOI: https://doi.org/10.1016/j.jns.2021.117452

Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders

Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype–phenotype correlations. Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene. Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29*), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern. Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype–phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype–phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome.

Reference: Journal of Translational Medicine volume 17, Article number: 290 (2019) Full text

Association of relapsing oral ulcers and benign fasciculations. Can they be related to gluten sensitivity?

A 32-years-old male patient developed relapsing episodes presenting with oral ulcers and spread fasciculations. Neurological exams and electromyographic studies performed over 7 years follow-up did not reveal any abnormal sign other than difuse fasciculations, concluding it is a case of benign fasciculations. Imaging and laboratory studies did not show any relevant abnormal findings apart from unespecific autoimmune parameters and food allergies, suggesting an immuneallergic background. Albeit clinical improvement was achieved after empiric gluten free diet, the hypothesis linking the clinical picture to gluten sensitivity has not been proven. Up to our knowledge, this is the first report of a case with relapsing oral ulcers and benign fasciculations.

Reference: Menéndez-González M, Milla A. Brotes recurrentes de aftosis oral y fasciculaciones benignas ¿Posible relación con sensibilidad al gluten? Archivos de Medicina 2016;12(1):8 (Full text, in Spanish) 

Antithyroid psychosis

The association of thyroid disorders and thyroid-related treatments with psychiatric disorders is well known. What is not recognized yet is if antithyroid antibodies may cause psychosis in the absence of encephalopathy and thyroid dysfunction. I report here the cases of 4 patients who developed de-novo psychosis where I found they had high titers of antithyroid antibodies, both antithyroglobulin and anti-TPO antibodies. All the four patients were women aging 39-64 years old, without history of psychiatric disorders until they started with an isolated and flourished picture of psychosis. Remarkably, thyroid function was normal. All cases showed positive CSF thyroid antibodies and all recovered after steroid therapy.

I propose to coin the term “antithyroid psychosis” to denote cases of de-novo psychosis with antithyroid antibodies in the absence of encephalopathy. The main importance of diagnosing these cases is that it is a tractable disorder. Screening for antithyroid antibodies should be considered in all patients with de-novo psychosis or postpartum psychosis. 

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Panic attack triggering myocardial ischemia documented by myocardial perfusion imaging study. A case report

Background

Chest pain, a key element in the investigation of coronary artery disease is often regarded as a benign prognosis when present in panic attacks. However, panic disorder has been suggested as an independent risk factor for long-term prognosis of cardiovascular diseases and a trigger of acute myocardial infarction.

Objective

Faced with the extreme importance in differentiate from ischemic to non-ischemic chest pain, we report a case of panic attack induced by inhalation of 35% carbon dioxide triggering myocardial ischemia, documented by myocardial perfusion imaging study.

Discussion

Panic attack is undoubtedly a strong component of mental stress. Patients with coronary artery disease may present myocardial ischemia in mental stress response by two ways: an increase in coronary vasomotor tone or a sympathetic hyperactivity leading to a rise in myocardial oxygen consumption. Coronary artery spasm was presumed to be present in cases of cardiac ischemia linked to panic disorder. Possibly the carbon dioxide challenge test could trigger myocardial ischemia by the same mechanisms.

Conclusion

The use of mental stress has been suggested as an alternative method for myocardial ischemia investigation. Based on translational medicine objectives the use of CO2 challenge followed by Sestamibi SPECT could be a useful method to allow improved application of research-based knowledge to the medical field, specifically at the interface of PD and cardiovascular disease. 

Soares-Filho GLF, Mesquita CT, Mesquita ET, Arias-Carrión O, Machado S, Menéndez-González MM, Valença A and Nardi AE Panic attack triggering myocardial ischemia documented by myocardial perfusion imaging study. A case report. International Archives of Medicine 2012, 5:24 Full text

Refractory epilepsy and crossed cerebellar diaschisis

Article in Spanish.

Reference:
R. Ribacoba, M. Menéndez, J. Salas-Puig. Refractory epilepsy and crossed cerebellar diaschisis. Neurologia 24(3):211-213 (Full text, in Spanish)

A new de novo Notch3 mutation causing CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is one of the most common hereditary forms of stroke, and migraine with aura, mood disorders, or dementia, are also frequently found in these patients. Missense mutations in the Notch3 gene that create or destroy cysteine residues, have been found in most cases with a family history of the disease, although a few sporadic cases harbouring Notch3 mutations have also been described. Here, we describe a 44-year-old patient with clinical features of CADASIL who was a carrier of a new Notch3 mutation: cys128-->gly. Both parents were alive and healthy, and negative for the mutation. This case illustrates the interest of analysing the Notch3 gene in cases with clinical features of CADASIL, even in the absence of a family history of the disease.

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Reference: Coto E, Menéndez M, Navarro R, García-Castro M, Alvarez V. A new de novo Notch3 mutation causing CADASIL. Eur J Neurol. 2006 Jun;13(6):628-31.

Wallenberg's syndrome secondary to dissection of the vertebral artery caused by chiropractic manipulation

INTRODUCTION: Chiropractic manipulations of the cervical region are techniques that are used more and more frequently to treat a number of osteomuscular pathologies, but can give rise to important complications, such as the dissection of the cervical arteries. Dissection of the vertebral artery generally presents as alternating syndromes, of which Wallenberg s syndrome, either complete or incomplete, is the most frequent. In this paper we review the literature published to date on the pathogenesis, risk factors, clinical features, chronopathology, diagnosis, treatment and prognosis of this complication.
CASE REPORT: We describe the case of a young patient who suffered from incomplete Wallenberg s syndrome a few hours after a single session of cervical chiropractic manipulation, and we also show the resonance images that were used to support the diagnosis.

Reference: Menéndez-González M, García C, Suárez E, Fernández-Díaz D, Blázquez-Menes B. Rev Neurol. Wallenberg's syndrome secondary to dissection of the vertebral artery caused by chiropractic manipulation. 2003;37(9):837-9. Free ful text (in Spanish)

Exacerbation of Lewy bodies dementia due to memantine

INTRODUCTION: Lewy body dementia (DLB) is common but frequently misdiagnosed as Alzheimer's disease plus delirium or parkinsonism. Drugs used in this disorder can cause exacerbations: neuroleptic medication is relatively contraindicated because some patients show severe neuroleptic sensitivity, antiparkinsonian medication has the potential to exacerbate psychotic symptoms, and even cholinesterase inhibitors, while relatively safe, have provoked adverse responses in some DLB patients. There are few data available about the use of memantine in DLB.
CASE REPORT: A 74-year-old man was diagnosed with Alzheimer disease and parkinsonism. After memantine was started he developed severe fluctuations in awareness, visual hallucinations, agitation, and worsened parkinsonism. When he was evaluated thoroughly, the diagnosis was revised to Lewy body dementia, leading to changes in treatment that were associated with dramatic improvement in the patient's mental status.
CONCLUSIONS: In our patient, motor and cognitive symptoms worsened with memantine treatment; these resolved after memantine was discontinued.

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Reference:
Menendez-Gonzalez M, Calatayud MT, Blazquez-Menes B. Exacerbation of Lewy bodies dementia due to memantine. J Alzheimers Dis. 2005 Dec;8(3):289-91

Cerebral gas embolism caused by pleural fibrinolytic treatment

BACKGROUND AND PURPOSE: Intrapleural fibrinolytic therapy is a technique used to treat empyemas and parapneumonic effusions. Cerebral air embolism is an unusual potentially severe complication of this technique.

SUMMARY OF CASE: A patient with parapneumonic pleural effusion underwent pleural lavage with streptokinase when he suddenly demonstrated focal neurological signs and seizures. The CT revealed multiple air-isodense spots in right hemisphere of the brain, suggesting cerebral air embolism. As a result of early diagnosis and emergency hyperbaric oxygenation, the patient recovered without delayed sequelae.

CONCLUSIONS: Air embolism is a potentially severe complication which can occur during fibrinolytic pleural lavage, and clinicians should be aware of this risk. In this context, the onset of acute focal neurological signs or seizures should suggest the possibility of air embolism and lead to the transfer of the patient close to a hyperbaric facility within a few hours.

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Reference:
Menéndez-González M, Oliva-Nacarino P, Alvarez-Cofiño A. Cerebral gas embolism caused by pleural fibrinolytic treatment. Stroke. 2007 Sep;38(9):2602-4. Epub 2007 Aug 2.

Partial trisomy 13q22-qter associated to leukoencephalopathy and late onset generalised epilepsy.

The partial trisomy 13q.22 is an uncommon chromosomopathy. We present a case with a partial trisomic component 13q22 and a monosomic component 5p15 from paternal origin. This patient developed early menopause and major neurological disorders as leukoencephalopathy, late onset generalised epilepsy and stroke. She also had fatty acids disturbances and their potential relation to the neurological disorders and early menopause is discussed. The presented case illustrates the phenotype of 13q22-qter in adult age and reaffirms the importance of studying the karyotype of any patient with seizures or leukoencephalopathy particularly when there are associated other clinical features including stroke at a young age, fatty acids disturbances, microcephaly, hypotelorism, short neck, hemangiomata, short fingers or distal swell in thumbs.

Free full text

Reference:
Ribacoba R, Menendez-Gonzalez M, Hernando I, Salas J, Giros ML. Partial trisomy 13q22-qter associated to leukoencephalopathy and late onset generalised epilepsy. Int Arch Med. 2008 Apr 29;1(1):5.