Quality of life is not impaired in patients with hereditary neuropathy with liability to pressure palsies.
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Adult↗
Biomedical subjects
T Cavallaro
Publications and source records attributed to T Cavallaro.
Variables influencing quality of life and disability in Charcot Marie Tooth (CMT) patients: Italian multicentre study.
The purpose of this study was to assess the variables that influence quality of life (QoL) and disability in patients with Charcot-Marie-Tooth disease (CMT). We performed a prospective multicentre study using validated clinical disability and QoL measurements. Multivariate analysis was performed using QoL as a dependent variable and duration of symptoms, age, gender and CMT type, depression and disability measurements as independent variables. We enrolled 211 patients. QoL was highly significantly deteriorated with respect to the Italian normative sample. The physical aspect of QoL was mainly related to disability but it does not increase with the age, probably because of an adaptation between expectation and reality. The mental QoL is influenced by depression (hence we have to consider this aspect approaching CMT patients). Moreover, we observed that women complained of more severe symptoms than men. Finally, some CMT subtypes are related to more severe bodily pain symptoms than others. Multiperspective assessment of CMT showed new aspects of this disease, mainly regarding (1) differences between men and women and (2) the crucial role of pain and depression.
Adolescent↗
Segmental conduction abnormalities and myelin thickenings in Val102/fs null mutation of MPZ gene.
The authors report in patients with Val102/fs null mutation a possibly age dependent variability of clinical and electrophysiologic phenotype, segmental conduction abnormalities mainly in ulnar nerves at the elbow, and excessive myelin foldings and thickenings. The authors hypothesize that myelin thickenings at the paranodal region, in concurrence with compression at usual entrapment sites or minor repetitive trauma, may induce segmental conduction abnormalities.
Adult↗
Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E.
The axonal type 2 Charcot-Marie-Tooth disease (CMT2) is phenotypically poorly characterized. Here the authors report a family with a Pro22Ser mutation in the neurofilament-light gene (NF-L; CMT2E) manifesting electrophysiologically as the demyelinating type 1 CMT (CMT1) and pathologically as an axonopathy with giant axons and accumulation of disorganized NF. NF-L should be investigated in CMT2 as well as in CMT1 not associated with the usual genes PMP22, Cx32, and P0.
Adult↗
Inter-nerves and intra-nerve conduction heterogeneity in CMTX with Arg(15)Gln mutation.
OBJECTIVE: In X-linked Charcot-Marie-Tooth disease (CMTX), electrophysiological and histopathological studies have suggested either a demyelinating or an axonal polyneuropathy. We report a CMTX family with a striking heterogeneity of nerve conductions between and within nerves. METHODS: Two men and one woman have been studied by conduction velocities, sural nerve biopsy with morphometry (one man) and DNA analysis. RESULTS: In both men motor conduction velocities were slowed in the demyelinating range, conduction velocity differences among nerves in the same subject varied from 13 to 24 m/s, and distal median compound muscle action potential (CMAP) amplitudes were 3-5 times reduced compared to ulnar CMAPs. Abnormal area reduction or excessive temporal dispersion of proximal CMAP was present in at least two nerves in all patients. Sural nerve biopsy showed reduction of large myelinated fibres, cluster formations, occasional onion bulbs. Teased fibres study revealed short internodes for fibre diameter, enlarged Ranvier nodes but no evidence of segmental demyelination and remyelination. DNA analysis showed an Arg(15)Gln mutation in connexin32 gene in all patients. CONCLUSIONS: In this family conduction slowing and segmental conduction abnormalities, in absence of morphological evidence of de-remyelination, may be related to short internodes, widened Ranvier nodes and the specific effect of the mutation. The occurrence in some CMTX patients of a non uniform involvement between and within nerves, as in acquired demyelinating neuropathies, should be kept in mind to avoid misdiagnoses.
Adult↗
Charcot-Marie-Tooth disease with giant axons: a clinicopathological and genetic entity.
The authors report an Italian family with autosomal-dominant Charcot-Marie-Tooth disease (CMT) in which there were giant axons in the sural nerve biopsy. Linkage to the known CMT2 loci (CMT2A, CMT2B, CMT2D, CMT2F) and mutations in the known CMT2 genes (Cx32, MPZ, NEFL), GAN, NEFM, and CMT1A duplication/HNPP deletion were excluded. This family with CMT and giant axons has a pathologic and genetic entity distinct from classic CMT.
Adult↗
MELAS: clinical phenotype and morphological brain abnormalities.
We describe the clinical and neuropathological findings of three unrelated autopsy cases of MELAS harboring the A3243G transition in the mitochondrial DNA (mtDNA). Using immunohistochemical techniques, we studied the expression of several subunits of the respiratory chain in various brain regions from the same cases. In all three cases there was a reduced immunocytochemical staining for mtDNA-encoded subunits of the respiratory chain, confirming the presence of a defective mitochondrial protein synthesis in this disease. Mitochondrial abnormalities were mostly confined to multiple areas of different size and shape, in agreement with the focal character of the brain pathology in MELAS, and were most prominent in the cerebral cortex, providing a morphological contribution to the explanation of the cognitive regression of the patients. Immunoreactivity for mtDNA-encoded subunits was reduced in the walls of many pial and intracerebral arterioles of different brain regions but there was no clear correlation between territories of affected vessels and distribution of the histological and immunohistochemical lesions. Cerebral focal lesions in MELAS might have a metabolic nature and several pathogenetic mechanisms might be involved in the genesis of stroke-like episodes when there is a local increased ATP demand.
Adenosine Triphosphatases↗
Hereditary neuropathy with liability to pressure palsies: electrophysiological and genetic study of a family with carpal tunnel syndrome as only clinical manifestation.
Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disease characterized by recurrent sensory or motor manifestations. The molecular basis of HNPP is a deletion on chromosome 17p11.2. We studied a family (father, 61 years; mother, 55 years; 6 children of mean age 25.3 years) showing symptoms of carpal tunnel syndrome in 4 members (the parents and 2 sons). No one of them reported episodes of nerve palsy. In all the patients, except the mother and the younger son, electrophysiologic evaluation showed a sensorimotor polyneuropathy with delayed sensorimotor latencies. Genetic analysis was carried out in the parents and the eldest son. The 17p11.2 deletion was detected in the father and son, indicating paternal transmission of the disease. Clinical manifestations of HNPP may be atypical. Sometimes there is no history of acute nerve palsy, as in this family. For this reason, the frequence of HNPP might be underestimated. Electrophysiological examination is of great importance for the diagnosis of HNPP. Genetic analysis is a rapid and reliable diagnostic tool that can be combined with simplified electrophysiological examination, avoiding the need for nerve biopsy. In conclusion, the diagnosis of HNPP should be invoked in early onset entrapment neuropathies.
Adolescent↗
Atypical familial motor neuropathy in patients with mutant TTR Ile68Leu.
Two sisters from an Italian family shared progressive motor symptoms, preceding the onset of sensory and autonomic disturbances. The familial occurrence of axonal and slowly progressive polyneuropathy led us to consider these patients as candidates for TTR molecular analysis. We found a missense mutation causing Ile68Leu TTR substitution in both. The aims of this work are to report the possibility of a motor onset of amyloid polyneuropathy and to suggest the search for TTR mutations in familial cases of axonal polyneuropathy. Second, to stress the possible occurrence of amyloid within the spinal canal as the potential pathogenesis and responsible for motor presentation.
Adult↗
A somatic and germline mosaic mutation in MPZ/P(0) mimics recessive inheritance of CMT1B.
OBJECTIVE: To identify the molecular basis of a demyelinating Charcot-Marie-Tooth disease type 1 (CMT1) with presumed autosomal recessive inheritance. BACKGROUND: CMT1, an inherited motor and sensory neuropathy with low nerve conduction velocities, is caused by dominantly inherited mutations in the genes of the peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ/P(0)), and early growth response 2 transcription factor (EGR2/Krox-20). PATIENTS AND METHODS: Two young sisters born of clinically and electrophysiologically healthy parents had a severe CMT1 neuropathy of presumed autosomal recessive inheritance. The older sister underwent a nerve biopsy. The authors analyzed PMP22, MPZ/P(0), and EGR2/Krox-20 by automated direct nucleotide sequencing. For rapid mutation detection, they determined the restriction-fragment-length polymorphisms for TaqI in the fluorescein-labeled target DNA sequence amplified by PCR. RESULTS: Nerve biopsy disclosed a demyelinating and remyelinating neuropathy with onion bulb formations. Both sisters had a novel heterozygous G308-->A transition of MPZ/P(0) without any mutation of PMP22 or EGR2/Krox-20. The G308-->A transition was a nonconservative mutation that changed a glycine into a glutamate at the amino acid residue 74 in the extracellular domain of the mature MPZ/P(0). None of 50 healthy controls had the mutation. The healthy mother had a low amount of the mutation in blood (congruent with 20%) as well as in skin, buccal epithelium, and hairs (30%). Because the healthy mother carried clones of somatic mutant cells and had transmitted the G308-->A transition to the affected daughters, she also harbored germline mutant cells. CONCLUSION: In hereditary demyelinating neuropathies, somatic and germline mosaicism of dominant mutations in the myelin protein genes may mimic autosomal recessive inheritance.
Adolescent↗
Increased expression of the normal cellular isoform of prion protein in inclusion-body myositis, inflammatory myopathies and denervation atrophy.
The cellular isoform of the prion protein (PrPc) is a glycosylphosphatidylinositol-anchored glycoprotein, normally expressed in neural and non-neural tissues, including skeletal muscle. In transmissible spongiform encephalopathies, or prion diseases, PrPc, which is soluble in nondenaturing detergent and sensitive to proteinase K (PK)-treatment, represents the molecular substrate for the production of a detergent-insoluble and PK-resistant isoform, termed PrP(Sc). In human prion diseases, PrP(Sc) accumulation occurs only in brain tissues, with the exception of new variant Creutzfeldt-Jakob disease, where PrP(Sc) is also detected in lymphoid tissues. Increased amounts of prion protein expression and deposition have been described in pathological muscle fibers of two human muscle disorders, called sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy, but it is unknown whether accumulated prion protein reflects normal PrPc or PrP(Sc). We investigated the biochemical characteristics of prion protein in normal human muscle, s-IBM, other inflammatory myopathies and denervation atrophy. We report that 1) both the glycoform profile and size of the normal muscle PrPc are different from those of human brain PrPc; 2) in addition to s-IBM, increased PrPc expression is seen in polymyositis, dermatomyositis and neurogenic muscle atrophy, but PrPc glycoforms are unchanged; 3) only the normal PrPc isoform, and not PrP(Sc), is detected in s-IBM. The present results exclude that s-IBM is a prion disease.
Adult↗
PMP22 related congenital hypomyelination neuropathy.
The peripheral myelin protein 22 (PMP22) is a tetraspan membrane protein which is localised in the compact myelin of the peripheral nerves. In fibroblasts, where it was originally identified as growth arrest related factor 3 (Gas3), PMP22 has been shown to modulate cell proliferation; in the peripheral nervous system its roles are still debated. The duplication of PMP22 is the most common cause of the demyelinating form of the autosomal dominant Charcot-Marie-Tooth neuropathy (CMT1A); rarer missense mutations of PMP22 also cause CMT1A or severe dehypomyelinating neuropathies of infancy grouped under the heading of Dejerine-Sottas syndrome (DSS). Here, a sporadic patient affected with DSS is described; nerve biopsy disclosed a picture of hypomyelination/amyelination with basal laminae onion bulbs and no florid demyelination and it was consistent with congenital hypomyelination neuropathy (CHN); molecular analysis disclosed a novel point mutation of PMP22 that causes a non-conservative arginine for cysteine substitution at codon 109, in the third transmembrane domain. CHN is the rarest and severest form of DSS and it is thought to reflect dysmyelination rather than demyelination. The reported case suggests that missense point mutations may alter a putative role of PMP22 in modulating Schwann cell growth and differentiation.
Adolescent↗
Focally folded myelin in Charcot-Marie-Tooth neuropathy type 1B with Ser49Leu in the myelin protein zero.
Charcot-Marie-Tooth disease type 1 B (CMT1B) is a demyelinating neuropathy caused by mutations in the myelin protein zero (P0) gene (MPZ). A few cases of CMT1B were recently found to be characterized by focally folded myelin sheaths in nerve biopsy specimens; the significance of this association is unknown. Here, we describe two unrelated pedigrees harboring a heterozygous Ser49Leu substitution in P0ex. In both pedigrees, the mutation caused a late-onset, relatively mild CMT1B; in one pedigree, two patients had atrophy of peroneal muscles but hypertrophy of the gastrocnemius muscles. The sural nerve biopsy performed in the two index cases revealed an identical chronic demyelinating and remyelinating neuropathy dominated by focal foldings of the myelin sheath shaped either as tomacula or as out/infoldings. The report adds Ser49Leu to the mutations of P0ex associated with focally folded myelin and provides strong evidence that such a structural alteration of the myelin sheath reflects a distinct pathogenetic mechanism in a subgroup of CMT1B.
Amino Acid Substitution↗
Painless fractures and thermoregulation disturbances in sensory-autonomic neuropathy: electrophysiological abnormalities and sural nerve biopsy.
We describe the case of a young girl suffering from thermoregulation disturbances, painless fractures and arthropathy since early childhood. The patient was diagnosed as having a hereditary sensory autonomic neuropathy. Although needle EMG, conventional nerve conduction studies and somatosensory evoked potentials gave normal results, sympathetic skin responses (SSRs) were absent. Sural nerve biopsy showed a substantial reduction in the number of small myelinated and unmyelinated fibers. We emphasize the importance of SSR testing in revealing a condition which is otherwise difficult to identify by electrophysiological techniques. The combined evidence of functional and morphological findings is strongly suggestive of selective peripheral nerve involvement.
Adolescent↗
Myelin uncompaction in Charcot-Marie-Tooth neuropathy type 1A with a point mutation of peripheral myelin protein-22.
BACKGROUND: The peripheral myelin protein-22 (PMP22) gene has four transmembrane domains, two extracellular loops, and a short cytoplasmic tail. Its roles in the peripheral nervous system remain unclear. The most common cause of Charcot-Marie-Tooth neuropathy type 1A (CMT1A) is a PMP22 gene duplication. Missense point mutations in the transmembrane domains are rare alternative causes that have undetermined pathogenetic mechanisms. OBJECTIVE: To investigate the phenotype-to-genotype correlations in a pedigree with unusual CMT1A. METHODS: We identified a pedigree with an autosomal dominant motor-sensory neuropathy and severely reduced nerve conduction velocities who did not have the PMP22 duplication. Specimens from sural nerve biopsies from two patients of different ages were evaluated morphometrically. By automated direct nucleotide sequencing we analyzed PMP22 and the gene of the major structural myelin protein zero (P0). RESULTS: Nucleotide 159 of PMP22 showed an A-to-T heterozygous mutation, predicted to cause an aspartate-to-valine substitution at codon 37 in the first extracellular loop of the protein. The mutation co-segregated with the disease in the pedigree and was absent in 80 healthy controls. The histopathologic phenotype was a de-remyelinating neuropathy with onion bulb formations, characterized by prominent uncompaction of the myelin sheath in the majority of fibers and by frequent tomacula. CONCLUSION: We have described a novel mutation in the first extracellular loop of PMP22 associated with an atypical CMT1A that overlaps pathologically with CMT1B caused by point mutations in the extracellular domain of P0.
Adult↗
Mitochondrial G8363A mutation presenting as cerebellar ataxia and lipomas in an Italian family.
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Adult↗
Congenital hypomyelination neuropathy with Ser72Leu substitution in PMP22.
We describe a patient with congenital hypomyelination neuropathy. The pathological and morphometrical findings in the sural nerve biopsy were consistent with a defect of myelin formation and maintenance. Direct sequence analysis of the genomic regions coding the peripheral myelin proteins P0 and PMP22 disclosed a heterozygous missense point mutation that leads to a Ser72Leu substitution in the second transmembrane of PMP22. Codon 72 mutations of PMP22 are associated with different phenotypes encompassing the Dejerine-Sottas syndrome and including congenital hypomyelination neuropathy.
Amino Acid Substitution↗
Novel mutation of the P0 extracellular domain causes a Déjérine-Sottas syndrome.
A patient is described with a Déjérine-Sottas syndrome caused by a novel heterozygous Cys(98)Tyr mutation in the extracellular domain of the major peripheral myelin protein zero (P0ex). Homotypical interactions between P0ex tetramers of apposed extracellular faces of the Schwann cell membrane play a crucial part in myelin compaction. The amino acid change disrupts a unique disulphide bond that stabilises the immunoglobulin-like structure of P0ex and it is predicted to cause severe dehypomyelination through dominant negative effects on the wild type protein.
Adult↗