Background and purpose
Dominantly inherited GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene have recently been shown to cause spinocerebellar ataxia 27B (SCA27B). We aimed to ...study the frequency and phenotype of SCA27B in a cohort of patients with unsolved late‐onset cerebellar ataxia (LOCA). We also assessed the frequency of SCA27B relative to other genetically defined LOCAs.
Methods
We recruited a consecutive series of 107 patients with LOCA, of whom 64 remained genetically undiagnosed. We screened these 64 patients for the FGF14 GAA repeat expansion. We next analysed the frequency of SCA27B relative to other genetically defined forms of LOCA in the cohort of 107 patients.
Results
Eighteen of 64 patients (28%) carried an FGF14 (GAA)≥250 expansion. The median (range) age at onset was 62.5 (39–72) years. The most common clinical features included gait ataxia (100%) and mild cerebellar dysarthria (67%). In addition, episodic symptoms and downbeat nystagmus were present in 39% (7/18) and 37% (6/16) of patients, respectively. SCA27B was the most common cause of LOCA in our cohort (17%, 18/107). Among patients with genetically defined LOCA, SCA27B was the main cause of pure ataxia, RFC1‐related disease of ataxia with neuropathy, and SPG7 of ataxia with spasticity.
Conclusion
We showed that SCA27B is the most common cause of LOCA in our cohort. Our results support the use of FGF14 GAA repeat expansion screening as a first‐tier genetic test in patients with LOCA.
Parkinson's disease (PD) is characterized by a great clinical heterogeneity. Nevertheless, the biological drivers of this heterogeneity have not been completely elucidated and are likely to be ...complex, arising from interactions between genetic, epigenetic, and environmental factors. Despite this heterogeneity, the clinical patterns of monogenic forms of PD have usually maintained a good clinical correlation with each mutation once a sufficient number of patients have been studied. Mutations in LRRK2 are the most commonly known genetic cause of autosomal dominant PD known to date. Furthermore, recent genome-wide association studies have revealed variations in LRRK2 as significant risk factors also for the development of sporadic PD. The LRRK2-R1441G mutation is especially frequent in the population of Basque ascent based on a possible founder effect, being responsible for almost 50% of cases of familial PD in our region, with a high penetrance. Curiously, Lewy bodies, considered the neuropathological hallmark of PD, are absent in a significant subset of LRRK2-PD cases. Indeed, these cases appear to be associated with a less aggressive primarily pure motor phenotype. The aim of our research is to examine the clinical phenotype of R1441G-PD patients, more homogeneous when we compare it with sporadic PD patients or with patients carrying other LRRK2 mutations, and reflect on the value of the observed correlation in the genetic forms of PD. The clinical heterogeneity of PD leads us to think that there may be as many different diseases as the number of people affected. Undoubtedly, genetics constitutes a relevant key player, as it may significantly influence the phenotype, with differences according to the mutation within the same gene, and not only in familial PD but also in sporadic forms. Thus, extending our knowledge regarding genetic forms of PD implies an expansion of knowledge regarding sporadic forms, and this may be relevant due to the future therapeutic implications of all forms of PD.
The autoimmune GFAP astrocytopathy has been associated with meningoencephalomyelitis that usually responds to glucocorticoids. We report a 20-year-old man that developed an acute and severe ...meningoencephalomyelitis with remarkable CNS hyperexcitability and oculogyric crises. CSF analysis showed hypoglycorrhachia, pleocytosis, elevated ADA, and CSF-immunofluorescence characteristic of autoimmune GFAP astrocytopathy. MRI showed lesions at thalamus, corpus-callosum, dorsal pons and dentate nucleus with associated myelitis. Immunotherapy led to a full recovery, although MRI activity was observed at follow-up. CNS hyperexcitability, typically seen in other immune-mediated syndromes, represents a novel presenting form to be included as part of the clinical spectrum of this entity.
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•A rapid presumption diagnosis of botulism should be made based on key symptoms-signs.•Post exercise facilitation represents a simple and reliable diagnostic test.•Antitoxin may not be necessary in ...patients with late-presenting mild clinical picture.
Botulism is a life-threatening presynaptic disorder of the neuromuscular transmission produced by the neurotoxin elaborated by the botulinum neurotoxin-producing clostridia. We describe the management of a case series of 14 patients, members of 5 different families that were exposed to home-canned tuna and developed symptoms compatible with a mild clinical presentation of foodborne botulism. The electrophysiological study of the index case represented a reliable diagnostic test as it demonstrated a slight presynaptic dysfunction of the neuromuscular junction. Definite diagnosis was later confirmed by microbiological tests. Out of 14, only 3 patients presenting with a shorter period from symptom onset and with signs of multiple cranial neuropathies received botulinum antitoxin. All the patients remained stable and recovered progressively. Treatment with antitoxin may not be necessary in patients with late-presenting disease and mild and stable clinical picture.
Cerebral venous thrombosis (CVT) is characterized by its variety of neurological manifestations and difficulty in diagnosis. In subacute cases, the main symptoms are secondary to increased ...intracranial pressure. This condition is associated with an extensive range of medical disorders, but only 2% are caused by a CNS infection in recent series. We report a 45-year-old patient, with no previous medical history, who developed a syndrome of increased intracranial pressure as the presentation of a cryptococcal meningoencephalitis (CM) complicated with a CVT. The patient was first diagnosed of a CVT, and later on, the VIH infection and the CM diagnosis were made. Despite being treated with anticoagulation, liposomal amphotericin B, and a therapeutic lumbar puncture, the patient continued to deteriorate and suffered a respiratory arrest secondary to the increased intracranial pressure, with subsequent brain death. Cryptococcus is an infrequent cause of CNS infection in developed countries, despite being the most frequent cause of meningits in adults in several countries with high rates of HIV infection. CVT is a very rare complication of CM which can contribute to worsen the increased intracranial pressure and in consequence, its prognosis and outcome. A high level of suspicion is needed for diagnosing CM as the underlying cause of CVT and the subsequent increased intracranial pressure should be managed exhaustively.
Cerebral cavernous malformations (CCMs) are dilated aberrant leaky capillaries located in the Central Nervous System. Familial CCM is an autosomal dominant inherited disorder related to mutations in ...KRIT1, Malcavernin or PDCD10. We show two unrelated families presenting familial CCM due to two new mutations in KRIT1 and PDCD10, producing truncated proteins. Clinical phenotype was highly variable among patients from asymptomatic individuals to diplopia, seizures or severe intracranial hemorrhage. PDCD10 patients usually show a more aggressive course and they frequently showed multiple meningiomas. This work provides evidence for the pathogenicity of two new mutations in CCM genes and supports previous findings regarding familial CCM and multiple meningiomas.
The COL4A1 mutation is a very rare monogenic cause of small vessel disease related to recurrent intracerebral hemorrhage. We report a family in which the index case presented with two intracerebral ...hemorrhages in the basal ganglia with severe periventricular leukoaraiosis and a cataract and vascular tortuosity in the ophthalmological study. His twin brother also had severe leukoaraiosis and multiple subcortical microhemorrhages as well as a congenital cataract and vascular tortuosity in the retina. The older sister had a porencephalic cyst and involvement of the periventricular white matter and intracerebral hemorrhage. In single-gene testing, all three were found to have the same COL4A1 mutation.
Intracerebral subcortical hemorrhages or microhemorrhages and severe subcortical leukoaraiosis in familial cases may be related to COL4 mutations.
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