Biomedical subjects

Karen Krajewski

Publications and source records attributed to Karen Krajewski.

7 recordsLinked to original sources

PubMed2005

SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation.

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies characterized by progressive weakness and atrophy of distal limb muscles. Recently, SIMPLE/LITAF was shown to be responsible for an autosomal dominant demyelinating form of CMT linked to 16p (CMT1C). Although two transcripts encoding different proteins (SIMPLE and LITAF) have been reported from the same gene, we could not confirm the existence of LITAF. Here we show that the LITAF transcript appears to result from a DNA sequencing error. We screened the SIMPLE gene for mutations in a cohort of 192 patients with CMT or related neuropathies, each of whom tested negative for other known genetic causes of CMT. In 16 unrelated CMT families we identified nine different nucleotide variations in SIMPLE that were not detected in control chromosomes. SIMPLE mutations can occur de novo, associated with sporadic CMT1 and may convey both demyelinating and axonal forms. Bioinformatics analyses and other observations of SIMPLE suggest that 1) it could be a member of the RING finger motif-containing subfamily of E3 ubiquitin ligases that are associated with the ubiquitin-mediated proteasome processing pathway, 2) it could interact through its PPXY motifs with a WW domain containing protein, for instance with NEDD4, an E3 ubiquitin ligase, and 3) it could interact through the PSAP motif with TSG10, a protein associated with endosomal multivesicular protein sorting. Since both SIMPLE and Hrs are endosomal proteins and have both PPXY and P(S/T)AP motifs, we hypothesize that SIMPLE, like Hrs, is potentially a clathrin adaptor aiding in the retention of ubiquitinated proteins on to the endosomes. Thus the potential E3 ubiquitin ligase activity of SIMPLE, alteration in its interactions with NEDD4 or TSG101, or changes in its properties as a clathrin coat adaptor may underlie the pathogenesis of Charcot-Marie-Tooth disease.

Adult↗

PubMed2004

Phenotypic clustering in MPZ mutations.

Myelin protein zero (MPZ) is a member of the immunoglobulin gene superfamily with single extracellular, transmembrane and cytoplasmic domains. Homotypic interactions between extracellular domains of MPZ adhere adjacent myelin wraps to each other. MPZ is also necessary for myelin compaction since mice which lack MPZ develop severe dysmyelinating neuropathies in which compaction is dramatically disrupted. MPZ mutations in humans cause the inherited demyelinating neuropathy CMT1B. Some mutations cause the severe neuropathies of infancy designated as Dejerine-Sottas disease, while others cause a 'classical' Charcot-Marie-Tooth (CMT) disease Type 1B (CMT1B) phenotype with normal early milestones but development of disability during the first two decades of life. Still other mutations cause a neuropathy that presents in adults, with normal nerve conduction velocities, designated as a 'CMT2' form of CMT1B. To correlate the phenotype of patients with MPZ mutations with their genotype, we identified and evaluated 13 patients from 12 different families with eight different MPZ mutations. In addition, we re-analysed the clinical data from 64 cases of CMT1B from the literature. Contrary to our expectations, we found that most patients presented with either an early onset neuropathy with signs and symptoms prior to the onset of walking or a late onset neuropathy with signs and symptoms at around age 40 years. Only occasional patients presented with a 'classical' CMT phenotype. Correlation of specific MPZ mutations with their phenotypes demonstrated that addition of either a charged amino acid or altering a cysteine residue in the extracellular domain caused a severe early onset neuropathy. Severe neuropathy was also caused by truncation of the cytoplasmic domain or alteration of an evolutionarily conserved amino acid. Taken together, these data suggest that early onset neuropathy is caused by MPZ mutations that significantly disrupt the tertiary structure of MPZ and thus interfere with MPZ-mediated adhesion and myelin compaction. In contrast, late onset neuropathy is caused by mutations that more subtly alter myelin structure and which probably disrupt Schwann cell-axonal interactions.

Adult↗

PubMed2004

Loss-of-function phenotype of hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) provides a human model to investigate the role of PMP22 in myelinated peripheral nerve, since the disease is caused by a deletion of one of the two PMP22 alleles. To systematically characterize the phenotype of HNPP, we prospectively evaluated the clinical features and electrophysiological findings in 17 genetically confirmed patients, 7 men and 10 women, ranging in age from 9 to 66 years (mean, 41 +/- 13). Fifteen symptomatic patients presented with episodes of transient focal weakness or sensory loss that were usually related to particular activities causing nerve compression, including stretching or minor repetitive focal trauma. No patient sought medical attention for symptoms of a symmetric polyneuropathy. Neurological examinations were either normal or mildly abnormal. Neither focal slowing of nerve conduction studies, nor reduction in compound muscle action potential (CMAP) or sensory nerve action potential (SNAP) amplitudes consistently predicted the site of symptoms. We conclude that the majority of patients with HNPP present with transient, recurrent, focal symptoms of weakness or sensory loss in the distribution of individual nerves or plexus, and that a diffuse symmetric sensorimotor polyneuropathy is an unusual presentation of HNPP. These studies suggest that the function of PMP22, at least in part, is to stabilize myelin so that it will be protected from injuries resulting from repetitive, minor trauma.

Adolescent↗

PubMed2003

Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy.

Proteolipid protein (PLP1) and its alternatively spliced isoform, DM20, are the major myelin proteins in the CNS, but are also expressed in the PNS. The proteins have an identical sequence except for 35 amino acids in PLP1 (the PLP1-specific domain) not present in DM20. Mutations of PLP1/DM20 cause Pelizaeus-Merzbacher Disease (PMD), a leukodystrophy, and in some instances, a peripheral neuropathy. To identify which mutations cause neuropathy, we have evaluated a cohort of patients with PMD and PLP1 mutations for the presence of neuropathy. As shown previously, all patients with PLP1 null mutations had peripheral neuropathy. We also identified 4 new PLP1 point mutations that cause both PMD and peripheral neuropathy, three of which truncate PLP1 expression within the PLP1-specific domain, but do not alter DM20. The fourth, a splicing mutation, alters both PLP1 and DM20, and is probably a null mutation. Six PLP1 point mutations predicted to produce proteins with an intact PLP1-specific domain do not cause peripheral neuropathy. Sixty-one individuals with PLP1 duplications also had normal peripheral nerve function. These data demonstrate that expression of PLP1 but not DMSO is necessary to prevent neuropathy, and suggest that the 35 amino acid PLP1-specific domain plays an important role in normal peripheral nerve function.

Adolescent↗

PubMed2003

Motor unit number estimate of distal and proximal muscles in Charcot-Marie-Tooth disease.

In order to determine the utility of motor unit number estimation (MUNE) in assessing axonal loss in chronic inherited neuropathies, we determined MUNEs in 54 patients with Charcot-Marie-Tooth (CMT) disease (29 patients with CMT-1A, 13 with CMT-X, and 12 with CMT-2) by using spike-triggered averaging (STA) of the ulnar-innervated abductor digiti minimi/hypothenar muscles (ADM) and the musculo-cutaneous innervated biceps/brachialis (BB) muscles. MUNEs were analyzed in relationship to the corresponding compound muscle action potential (CMAP) amplitudes as well as to clinical strength. Proximal muscles, which appeared strong clinically, had evidence of chronic denervation/reinnervation, although to a lesser extent than weak distal hand muscles, supporting the concept that axonal loss in CMT occurs in a length-dependent fashion. The reduction in ADM-MUNE strongly correlated with clinical weakness in the hand. Both the ADM-MUNE and BB-MUNE were abnormal more often than CMAP amplitude, probably reflecting extensive motor unit reconfiguration and enlargement that maintains CMAP amplitude despite severe motor unit loss. This study suggests that MUNE can assess motor unit loss in CMT and may better reflect axonal loss than CMAP amplitude. The STA technique of MUNE may be useful in longitudinal studies of proximal and distal motor unit changes in CMT.

Action Potentials↗

PubMed2002

Hereditary neuropathy with liability to pressure palsy: the electrophysiology fits the name.

BACKGROUND: Studies of patients with hereditary neuropathy with liability to pressure palsies (HNPP) have shown accentuated distal slowing along with nonuniform conduction abnormalities at segments liable to compression, suggesting a distal myelinopathy as an underlying pathophysiological mechanism. METHODS: We evaluated 12 patients with HNPP by standard nerve conduction studies and by conduction to more proximal muscles in the arm and leg. Three CMT1A patients and six healthy subjects also were evaluated as controls. RESULTS: Median and peroneal motor nerves in all HNPP patients showed prolonged distal motor latencies (DML) (mean +/- SE, 5.9 +/- 0.41 and 8.63 +/- 0.58 milliseconds), but the ulnar and tibial DML were minimally prolonged or normal (mean +/- SE, 3.87 +/- 0.16 and 5.66 +/- 0.24 milliseconds). DML to forearm flexor (median and ulnar nerves) or anterior tibial muscles (peroneal nerve) were also normal. CONCLUSION: Accentuated distal slowing is found primarily in median and peroneal nerve segments liable to pressure palsies or repetitive trauma. However, the ulnar and tibial nerves, which are less liable to compression, have minimal changes. In addition, distal latencies to more proximal muscles in the arm and leg do not have distal slowing. These findings do not support a distal myelinopathy as a determinant of the conduction abnormalities in HNPP.

Adolescent↗

PubMed2002

Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation.

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disorder that has been associated with alterations of several proteins: peripheral myelin protein 22, myelin protein zero, connexin 32, early growth response factor 2, periaxin, myotubularin related protein 2, N-myc downstream regulated gene 1 product, neurofilament light chain, and kinesin 1B. To determine the frequency of mutations in these genes among patients with CMT or a related peripheral neuropathy, we identified 153 unrelated patients who enrolled prior to the availability of clinical testing, 79 had a 17p12 duplication (CMT1A duplication), 11 a connexin 32 mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein 22 mutation, 1 an early growth response factor 2 mutation, 1 a periaxin mutation, 0 a myotubularin related protein 2 mutation, 1 a neurofilament light chain mutation, and 50 had no identifiable mutation; the N-myc downstream regulated gene 1 and the kinesin 1B gene were not screened for mutations. In the process of screening the above cohort of patients as well as other patients for CMT-causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22. The peripheral myelin protein 22 mutation W28R was associated with CMT1 and profound deafness. One patient with a CMT2 clinical phenotype had three myelin protein zero mutations (I89N+V92M+I162M). Because one-third of the mutations we report arose de novo and thereby caused chronic sporadic neuropathy, we conclude that molecular diagnosis is a necessary adjunct for clinical diagnosis and management of inherited and sporadic neuropathy.

Adolescent↗