Dominic B. Fee

Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes

Potassium channel mutations have been described in episodic neurological diseases. We report that K+ channel mutations cause disease phenotypes with neurodevelopmental and neurodegenerative features. In a Filipino adult-onset ataxia pedigree, the causative gene maps to 19q13, overlapping the SCA13 disease locus described in a French pedigree with childhood-onset ataxia and cognitive delay. This region contains KCNC3 (also known as Kv3.3), encoding a voltage-gated Shaw channel with enriched cerebellar expression. Sequencing revealed two missense mutations, both of which alter KCNC3 function in Xenopus laevis expression systems. KCNC3R420H, located in the voltage-sensing domain, had no channel activity when expressed alone and had a dominant-negative effect when co-expressed with the wild-type channel. KCNC3F448L shifted the activation curve in the negative direction and slowed channel closing. Thus, KCNC3R420H and KCNC3F448L are expected to change the output characteristics of fast-spiking cerebellar neurons, in which KCNC channels confer capacity for high-frequency firing. Our results establish a role for KCNC3 in phenotypes ranging from developmental disorders to adult-onset neurodegeneration and suggest voltage-gated K+ channels as candidates for additional neurodegenerative diseases.

Activated/effector CD4+ T cells exacerbate acute damage in the central nervous system following traumatic injury

CD4(+) helper T cells (Th) have been demonstrated to participate in the chronic phase of traumatic injury repair in the central nervous system (CNS). Here, we show that CD4(+) T cells can also contribute to the severity of the acute phase of CNS traumatic injury. We compared the area of tissue damage and the level of cellular apoptosis in aseptic cerebral injury (ACI) sites of C57BL/6 wild type and RAG1(-/-) immunodeficient mice. We demonstrate that ACI is attenuated in RAG1(-/-) mice compared to C57BL/6 animals. Adoptive transfer of CD4(+)CD62L(low)CD44(high) activated/effector T cells 24 h prior to ACI into RAG1(-/-) mice resulted in a significantly enhanced acute ACI that was comparable to ACI in the C57BL/6 animals. Adoptive transfer of CD4(+)CD62L(high)CD44(low) naive/non-activated T cells did not increase ACI in the brains of RAG1(-/-) mice. T cell inhibitory agents, cyclosporin A (CsA) and FK506, significantly decreased ACI-induced acute damage in C57BL/6 mice. These results suggest a previously undescribed role for activated/effector CD4(+) T cells in exacerbating ACI-induced acute damage in the CNS and raise a novel possibility for acute treatment of sterile traumatic brain injury.

Effects of progesterone on experimental spinal cord injury

Progesterone has been proposed to be protective to the central nervous system following injury. This study assessed progesterone supplementation in the setting of contusional spinal cord injury in male and female rats. Short-term (5 days of either 4 or 8 mg/kg progesterone) and long-term (14 days of either 8 or 16 mg/kg progesterone) therapy failed to show any significant alteration in locomotor functioning and injury morphometrics after 21 days. This study does not support progesterone as a potential therapeutic agent in spinal cord injury.

Myasthenia gravis associated with etanercept therapy

Etanercept is an antagonist of tumor necrosis factor alpha that was developed to treat rheumatoid arthritis. In this report we present a patient who developed myasthenia gravis while taking etanercept and had resolution of symptoms after stopping it. This is the first report of this potential side effect and is of additional interest, because etanercept has been proposed as a treatment for myasthenia gravis. Muscle Nerve, 2009

Kümmell's disease: a case report and literature review.

Study Design. A case report and literature review of Kümmell’s disease. Objective. To describe a case that meets modern criteria for Kümmell’s disease and discuss the literature on this. Summary of Background Data. Over 100 years ago, Hermann Kümmell described a condition in which patients sustained a “trivial” trauma, had an essentially asymptomatic period lasting weeks to months, then developed a painful, progressive angular kyphosis. Only with the advent of radiograph technology, and the radiographic demonstration of delayed vertebral body collapse, was this concept felt to be valid. There has been a renewed interest in this as a diagnostic entity. Methods. A patient is presented who developed worsening midback pain weeks after a minor fall. He subsequently was found to have T9, and T10 destructive vertebral body lesions. Results. Only after an extensive workup, including 3 biopsies of the affected area was the diagnosis of Kümmell’s disease considered and surgical treatment performed. Conclusion. Delayed vertebral body collapse, i.e., Kümmell’s disease, needs to be considered in any patient with recurrent or worsening spinal symptoms. Under-recognition of this condition leads to delayed diagnosis and treatment.

An autosomal dominant ataxia maps to 19q13: Allelic heterogeneity of SCA13 or novel locus?

The autosomal dominant spinocerebellar ataxias (ADCAs) represent a growing and heterogeneous disease phenotype. Clinical characterization of a three-generation Filipino family segregating a dominant ataxia revealed cerebellar signs and symptoms. After elimination of known spinocerebellar ataxia (SCA) loci, a genome-wide linkage scan revealed a disease locus in a 4-cM region of 19q13, with a 3.89 lod score. This region overlaps and reduces the SCA13 locus. However, this ADCA is clinically distinguishable from SCA13.

Phenotypic variability associated with Arg26Gln mutation in caveolin3

Caveolin3 (CAV3) is a protein associated with dystrophin, dystrophin‐associated glycoproteins, and dysferlin. Mutations in the CAV3 gene result in certain autosomal‐dominant inherited diseases, namely, rippling muscle disease (RMD), limb‐girdle muscular dystrophy type 1C (LGMD1C), distal myopathy, and hyperCKemia. In this report we show that a previously reported family with RMD has a mutation in the CAV3 gene. Affected individuals had either a characteristic RMD phenotype, a combination of RMD and LGMD1C phenotypes, or a LGMD1C phenotype, but one mutation carrier was asymptomatic at age 86 years. This phenotypic variability associated with mutations in CAV3 has been reported previously but only in a few families. It is important to remember the significant phenotypic variability associated with CAV3 mutations when counseling families with these mutations. These observations also suggest the presence of factors independent of the CAV3 gene locus that modify phenotype. Muscle Nerve 30: 375–378, 2004

Traumatic brain injury increases TGFβRII expression on endothelial cells

Transforming growth factor beta (TGFβ) modulates a variety of growth related functions following traumatic injury. The cellular response to TGFβ is predominantly mediated through TGFβ receptor I (TGFβRI) and receptor II (TGFβRII) on the cell surface and SMAD proteins intracellularly. We investigated the expression of TGFβ receptors in the acute and chronic phases of a traumatic cerebral injury (TCI) by immunohistochemistry and in cultures of murine brain microvascular endothelial (EN) cells using cytofluorimetry. Here, we report that TGFβRII expression significantly increases on brain endothelial cells in the chronic phase of TCI. SMAD3 and SMAD4 protein expression were also upregulated suggesting the activation of TGFβ receptor intracellular signaling. When TGFβRI and TGFβRII expression was studied in in vitro cultures of murine brain microvessel EN cells, TGFβRII showed increased expression on proliferating cells that are incorporating BrdU. These data show a differential expression of TGFβRI and TGFβRII on brain microvessel EN cells in the acute and chronic phases of TCI that might be associated with EN proliferation following injury.

Sporadic Creutzfeldt-Jakob disease presenting as nonconvulsive status epilepticus case report and review of the literature

Creutzfeldt-Jakob disease (CJD) is the most common transmissible human spongiform encephalopathy. Seizures and status epilepticus (SE) are an uncommon finding in CJD. We report a 64-year-old woman with rapid cognitive decline who had electroencephalographic (EEG) changes suggestive of nonconvulsive status epilepticus (NCSE). She was later diagnosed with sporadic CJD (sCJD). We also reviewed the literature for published cases on this topic. MEDLINE was employed to identify all published reports of CJD and SE. We identified 8 references with a total of 12 cases with CJD and NCSE. sCJD should be considered in the differential diagnosis of any patient who presents with rapid cognitive decline and EEG changes consistent with status epilepticus.

Unilateral calf hypertrophy seen in lumbosacral stenosis: case report and review of the literature.

Study Design. A case report of a patient with neurogenic unilateral calf hypertrophy and review of the literature are reported. Objectives. To provide further evidence that S1 radiculopathy is predisposed to develop neurogenic muscle hypertrophy. Summary of Background Data. Calf hypertrophy, specifically hypertrophy of the gastrocnemius muscle, is a rare but recognized presentation of S1 and less commonly L5 radiculopathies. The pathophysiology of this is incompletely understood. Methods. We present a 59-year-old patient with painless progressive distal right leg weakness and calf enlargement. Electrodiagnostic studies and MAGNETIC RESONANCE IMAGING scanning were performed to evaluate the extent and cause of radicular damage as the etiology for unilateral calf hypertrophy. Results. Examination and electrodiagnostic studies revealed right L5, right S1, and left L5 radiculopathies. Imaging studies demonstrated lumbar stenosis at L3–L4, L4–L5, and L5–S1 vertebral levels as well as L4–L5 and L5–S1 foraminal stenosis. After decompressive surgery the progressive nature of the patient’s symptomatology halted, and he had partial resolution of his deficits. Conclusion. Although the patient had bilateral L5 radiculopathies, he only had hypertrophy in the distribution of his right S1 radiculopathy. This supports the hypothesis that dysfunction of the S1 nerve root or its distribution is a predisposing factor to develop neurogenic muscle hypertrophy. Furthermore, patients presenting with unilateral calf hypertrophy need a careful diagnostic evaluation for S1 radiculopathy as well as to exclude asymmetric presentation of systemic neuromuscular conditions.