Late-onset hereditary axonal neuropathies.

BACKGROUND: Hereditary motor-sensory neuropathy or the Charcot-Marie-Tooth syndrome is known to represent considerable genetic heterogeneity. Onset is usually in childhood, adolescence, or young adulthood. The objective of this study was to define late-onset forms of the disorder. METHODS: A clinical and genetic study of families with uniformly late onset of peripheral neuropathy was performed in a university neurogenetics setting. RESULTS: Six families were identified with consistently late onset of a primarily axonal neuropathy. Median age at symptom onset was 57 years (range 35-85 years) of a mixed motor and sensory neuropathy with electrophysiologic characteristics of an axonal rather than demyelinating condition. There was a possible association with deafness. Two families showed autosomal dominant inheritance whereas four families had only one affected generation with an excess of males. An extensive mutation screen of nine genes known to cause Charcot-Marie-Tooth was negative. CONCLUSIONS: There are late-onset forms of hereditary axonal neuropathies. The genetic causes remain unknown and genetic heterogeneity within this entity is likely.

The clinical and genetic spectrum of spinocerebellar ataxia 14.

Spinocerebellar ataxia 14 (SCA14) is associated with missense mutations in the protein kinase C gamma gene (PRKCG), rather than a nucleotide repeat expansion. In this large-scale study of PRKCG in patients with ataxia, two new missense mutations, an in-frame deletion, and a possible splice site mutation were found and can now be added to the four previously described missense mutations. The genotype/phenotype correlations in these families are described.

Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C.

BACKGROUND: Charcot-Marie-Tooth (CMT) neuropathy is a heterogeneous group of inherited disorders of the peripheral nervous system. The authors recently mapped an autosomal dominant demyelinating form of CMT type 1 (CMT1C) to chromosome 16p13.1-p12.3. OBJECTIVE: To find the gene mutations underlying CMT1C. METHODS: The authors used a combination of standard positional cloning and candidate gene approaches to identify the causal gene for CMT1C. Western blot analysis was used to determine relative protein levels in patient and control lymphocyte extracts. Northern blotting was used to characterize gene expression in 1) multiple tissues; 2) developing sciatic nerve; and 3) nerve-crush and nerve-transection experiments. RESULTS: The authors identified missense mutations (G112S, T115N, W116G) in the LITAFgene (lipopolysaccharide-induced tumor necrosis factor-alpha factor) in three CMT1C pedigrees. LITAF, which is also referred to as SIMPLE, is a widely expressed gene encoding a 161-amino acid protein that may play a role in protein degradation pathways. The mutations associated with CMT1C were found to cluster, defining a domain of the LITAF protein having a critical role in peripheral nerve function. Western blot analysis suggested that the T115N and W116G mutations do not alter the level of LITAF protein in peripheral blood lymphocytes. The LITAF transcript is expressed in sciatic nerve, but its level of expression is not altered during development or in response to nerve injury. This finding is in stark contrast to that seen for other known genes that cause CMT1. CONCLUSIONS: Mutations in LITAF may account for a significant proportion of CMT1 patients with previously unknown molecular diagnosis and may define a new mechanism of peripheral nerve perturbation leading to demyelinating neuropathy.

Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes.

Charcot-Marie-Tooth Hereditary Neuropathy is a heterogeneous syndrome associated with mutations in several different genes including peripheral myelin protein 22, myelin P0, connexin 32, and early growth response 2. There is considerable variability in the phenotypic expression of this syndrome and the relationship of this variability to mutation genotypes requires extensive analysis. Here we describe the phenotypes and genotypes of four new mutations underlying the Charcot-Marie-Tooth syndrome and document segregation with disease. Four families with Charcot-Marie-Tooth were ascertained, examined, and evaluated electrophysiologically. Each family had peripheral blood DNA screened for mutations in myelin protein 22, myelin P0, and connexin 32. Two families were found with new mutations in the myelin P0 gene: S140T in the extracellular domain and K236del in the cytoplasmic domain. All families showed segregation of the mutations with the Charcot-Marie-Tooth phenotype as did a new family with the rare G163R mutation in the membrane domain. A 49-year-old man with the S140T mutation demonstrated conduction block on electrophysiological testing. A family with a novel S49P mutation in the connexin 32 gene had a neuropathy with very slow nerve conduction. These new mutations in the myelin P0 and connexin 32 genes help to clarify the pathophysiology of the clinical Charcot-Marie-Tooth syndrome. The S140T mutation in myelin P0 can be associated with conduction block and Charcot-Marie-Tooth should be part of the differential diagnosis of that phenomenon. Mutations in the cytoplasmic domain of myelin P0 can cause clinical neuropathy. The S49P mutation in the connexin 32 gene can produce aspects of a demyelinating type of X-linked hereditary neuropathy.

Clinical and pathological phenotype of the original family with Charcot-Marie-Tooth type 1B: a 20-year study.

Charcot-Marie-Tooth type 1B is an uncommon form of hereditary motor and sensory neuropathy caused by mutations in the P(0) myelin protein gene on chromosome 1. We report here a 20-year observation of 13 members of the first family with Charcot-Marie-Tooth disease to demonstrate linkage to chromosome 1 and now known to have a C270A mutation in the P(0) gene altering the extracellular domain of the protein. Affected individuals generally show an early age at onset, often indicated by delayed ability to walk. Proximal muscle weakness of the lower extremities is common and often marked, but the individuals remain ambulatory and there is no decrease in life span. Motor nerve conduction velocities of the fastest fibers are severely slowed (mean, 9-11 m/sec), even when compared with 3 families having Charcot-Marie Tooth type 1A (mean, 19-21 m/sec). Variability of disability between family members suggests that genetic and environmental factors in addition to the P(0) mutation play a role in the final phenotype. Nerve biopsy specimens demonstrate hypertrophy, onion bulb formation, loss of myelinated fibers, and occasional myelin thickening similar to that described in P(0) myelin knockout mice. Autopsy of the 92-year-old great-grandmother in this family demonstrated diffuse involvement of sensory and motor nerves, with loss of myelin in the posterior columns of the spinal cord and loss of anterior horn neurons but without other involvement of the central nervous system. This family demonstrates the long-term phenotypic consequences on the peripheral nervous system of a specific point mutation in the P(0) myelin gene.

Familial spastic paraparesis: evaluation of locus heterogeneity, anticipation, and haplotype mapping of the SPG4 locus on the short arm of chromosome 2.

Familial spastic paraparesis (SPG) is a clinically and genetically heterogeneous group of disorders. At least three loci have been implicated in autosomal dominant pure SPG and mutations in either of two loci may cause the X-linked form. Although the penetrance is high for all forms by age 60, there is wide variation in clinical characteristics, including age of onset. Two-point and multi-point linkage analyses in nine families provided supportive evidence that the most common form of SPG is linked to chromosome 2 (SPG4). Haplotype analysis localized the critical region to a 6 cM interval between D2S392 and D2S367. By haplotype analysis, the disease in at least one family does not appear to be linked to any of the presently known SPG loci, suggesting that there is at least one additional SPG gene. Evaluation at ages of onset in 11 families gave suggestive evidence for anticipation with mean age of onset in parents (41.3 years) being older than mean age of onset in children (26.9 years; P < 0.005).

Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A.

BACKGROUND: A general predisposition for vincristine-related neuropathy has been observed in persons with a family history of hereditary neuropathies. METHODS: In a retrospective case series, we investigated the possible association between the DNA rearrangement found in patients with Charcot-Marie-Tooth Disease Type 1A (CMT1A) and susceptibility to the neurotoxicity of vincristine. In selected patients and family members, we performed electrodiagnostic studies and analyzed DNA samples for 17p11.1-12 duplication associated with CMT1A. RESULTS: We describe three families with autosomal dominant CMT1, among whom a family member with a neoplastic disease suffered rapid onset, severe neuropathy after receiving initial doses of vincristine as a part of a routine chemotherapy protocol. All three families had at least one affected family member with 17p11.2-12 duplication. CONCLUSIONS: These cases show that 17p11.2-12 duplication predisposes patients to severe neurotoxicity from vincristine and that this drug should be avoided with patients with CMT1A. It is therefore essential to obtain a detailed family history for all oncology patients to screen for possible hereditary neuropathies. In patients with unexplained or preexisting familial neuropathy, testing for 17p11.2-12 duplication should be carried out prior to initiating vincristine therapy. Patients with other hereditary neuropathies may also be at risk for severe neurotoxic reactions.

Impotence associated with the Charcot-Marie-Tooth syndrome.

We report 7 men (ages 45-61 years) with impotence associated with the Charcot-Marie-Tooth syndrome (CMT). The range of onset of erectile dysfunction varied from 38 to 55 years of age. One patient had classic CMT 1A with autosomal dominant inheritance, slow motor nerve conduction velocities and the 17p DNA duplication. One had probable type-II hereditary motor and sensory neuropathy. None of the patients had diabetes. There was some benefit from papaverine injection therapy or penile implants. The association of impotence with CMT is likely to be more common than previously recognized.

The use of apolipoprotein CII as a genetic marker for myotonic dystrophy.

In five families we have confirmed the close linkage between the genes for myotonic dystrophy and apolipoprotein CII. The total maximum lod (log of the odds) score was 3.32 at 0 recombination. We demonstrate that the use of a Ban I restriction site polymorphism for apolipoprotein CII adds additional useful information when combined with the more commonly used Taq I polymorphism. The potential practical clinical use of these markers for the prenatal diagnosis of myotonic dystrophy is demonstrated.

Prevention of nervous system trauma from travel in motor vehicles.

Brain and spinal cord injuries are a frequent cause of death and long-term disability in motor vehicle accidents. Helmet use reduces death and head injury severity in motorcycle accidents. Proper use of child restraints can prevent death from falls and vehicle crashes. Auto lap and shoulder restraints, when in use, reduce death from accidents and falls from cars. Passive protections, such as air bags, vehicle design for crashworthiness, and automatic seatbelt systems are less available for economic reasons. Voluntary use of available devices is the remaining viable option. One-to-one education may help promote use of protective devices. The greatest impact lies in legislative requirements for self-protection. It is ethically justifiable to require use of devices such as child restraints, seatbelts, and motorcycle helmets to prevent death and disability.

Moving the patient in bed: effects on intracranial pressure.

Intracranial pressure (ICP) was measured in 20 patients before and after each of eight nursing care activities: turning the body to four positions, passive range of motion (arm extension and hip flexion), and rotation of the head to the right and to the left. Technically usable data was available for 18 patients. Mean ICP increased for at least five minutes in all patients after one of the four turns and in 88 percent after half the turns. Change in mean ICP with one of a pair of lateral or supine turns was strongly predictive of the direction of change (increase or decrease) of the other turn of the pair. Large increases in ICP occurred in the five patients for whom head rotation was done, while there was minimal change in ICP with both passive range of motion procedures. A cumulative increase in ICP occurred with activities spaced 15 minutes apart, regardless of the nature of the activity. No cumulative increase in ICP was found with procedures spaced at least one hour apart.